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Live 12:00 – 1:00 P.M  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : October 19, 2018

Reporter: Stephen J. Williams, Ph.D.

12.00 The Italian Mediterranean Diet as a Model of Identity of a People with a Universal Good to Safeguard Health?

Prof. Antonino De Lorenzo, MD, PhD.

Director of the School of Specialization in Clinical Nutrition, University of Rome “Tor Vergata”

It is important to determine how our bodies interacts with the environment, such as absorption of nutrients.

Studies shown here show decrease in life expectancy of a high sugar diet, but the quality of the diet, not just the type of diet is important, especially the role of natural probiotics and phenolic compounds found in the Mediterranean diet.

The WHO report in 2005 discusses the unsustainability of nutrition deficiencies and suggest a proactive personalized and preventative/predictive approach of diet and health.

Most of the noncommunicable diseases like CV (46%) cancer 21% and 11% respiratory and 4% diabetes could be prevented and or cured with proper dietary approaches

Italy vs. the US diseases: in Italy most disease due to environmental contamination while US diet plays a major role

The issue we are facing in less than 10% of the Italian population (fruit, fibers, oils) are not getting the proper foods, diet and contributing to as we suggest 46% of the disease

The Food Paradox: 1.5 billion are obese; we notice we are eating less products of quality and most quality produce is going to waste;

  •  growing BMI and junk food: our studies are correlating the junk food (pre-prepared) and global BMI
  • modern diet and impact of human health (junk food high in additives, salt) has impact on microflora
  • Western Diet and Addiction: We show a link (using brain scans) showing correlation of junk food, sugar cravings, and other addictive behaviors by affecting the dopamine signaling in the substantia nigra
  • developed a junk food calculator and a Mediterranean diet calculator
  • the intersection of culture, food is embedded in the Mediterranean diet; this is supported by dietary studies of two distinct rural Italian populations (one of these in the US) show decrease in diet
  • Impact of diet: have model in Germany how this diet can increase health and life expectancy
  • from 1950 to present day 2.7 unit increase in the diet index can increase life expectancy by 26%
  • so there is an inverse relationship with our index and breast cancer

Environment and metal contamination and glyphosate: contribution to disease and impact of maintaining the healthy diet

  • huge problem with use of pesticides and increase in celiac disease

12:30 Environment and Health

Dr. Iris Maria Forte, PhD.

National Cancer Institute “Pascale” Foundation | IRCCS · Department of Research, Naples, Italy

Cancer as a disease of the environment.  Weinberg’s hallmarks of Cancer reveal how environment and epigenetics can impact any of these hallmarks.

Epigenetic effects

  • gene gatekeepers (Rb and P53)
  • DNA repair and damage stabilization

Heavy Metals and Dioxins:( alterations of the immune system as well as epigenetic regulations)

Asbestos and Mesothelioma:  they have demonstrated that p53 can be involved in development of mesothelioma as reactivating p53 may be a suitable strategy for therapy

Diet, Tomato and Cancer

  • looked at tomato extract on p53 function in gastric cancer: tomato extract had a growth reduction effect and altered cell cycle regulation and results in apoptosis
  • RBL2 levels are increased in extract amount dependent manner so data shows effect of certain tomato extracts of the southern italian tomato (     )

Antonio Giordano: we tested whole extracts of almost 30 different varieties of tomato.  The tomato variety  with highest activity was near Ravela however black tomatoes have shown high antitumor activity.  We have done a followup studies showing that these varieties, if grow elsewhere lose their antitumor activity after two or three generations of breeding, even though there genetics are similar.  We are also studying the effects of different styles of cooking of these tomatoes and if it reduces antitumor effect

please see post https://news.temple.edu/news/2017-08-28/muse-cancer-fighting-tomatoes-study-italian-food

 

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BIO 2018! June 4-7, 2018 at Boston Convention & Exhibition Center

LIVE 2018 The 21st Gabay Award to LORENZ STUDER, Memorial Sloan Kettering Cancer Center, contributions in stem cell biology and patient-specific, cell-based therapy

HUBweek 2018, October 8-14, 2018, Greater Boston – “We The Future” – coming together, of breaking down barriers, of convening across disciplinary lines to shape our future

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Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases


Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals.  The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA).  The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA).  The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease.  There is also a long history of the measurement of  circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.

There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of

1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity.  Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.

There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke.  Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation.  A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium.   Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.

It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life.  Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association.  In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age.  The establishment of an epigenetic change is diluted in a diverse population.  There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.

This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series.  Below is a diagram of this volume in the series.

PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO:  Implementing Biomarker Programs ­ P Ridker PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
   Environmental Contributors
Implicated as Causing CVD
   Diet: Solids and Fluid Intake
and Nutraceuticals
   Physical Activity and
Prevention of CVD
   Psychological Stress and
Mental Health: Risk for CVD
   Correlation between
Cancer and CVD
PART 3  Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
    Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
     Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
     Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
     Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
    Preventive Medicine: Cardiovascular Diseases
    Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia,
DM, and possibly CAD
https://pharmaceuticalintelligence.com/2013/04/04/walking-and-running-similar-risk-reductions-for-hypertension-hypercholesterolemia-dm-and-possibly-cad/
    Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?
https://pharmaceuticalintelligence.com/2012/08/23/prevention-of-type-2-diabetes-is-bariatric-surgery-the-solution/
Gene-Therapy for CVD
Congenital Heart Disease/Defects
   Medical Etiologies: EBM – LEADING DIAGNOSES, Risks Pharmacogenomics for Cardio-
vascular Diseases
   Signaling Pathways     Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect
https://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
   Proteomics and Metabolomics      Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)
https://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
      SNPs in apoE are found to influence statin response
significantly. Less frequent variants in
PCSK9 and smaller effect sizes in SNPs in HMGCR
https://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

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Genome Jigsaws

Genome Jigsaws (Photo credit: dullhunk)

Sequencing became the household name.  In 2000s, it was thought to be the key of the Pandora’s box for cure.  Then, after completion of Human Genome Projects showed that there are less number of genes than expected.  This outcome induce to originate yet another set of sequencing programs and collaborations around the world, such as Human Protein Project, Human Microorganisms Projects, ENCODE, Transcriptome Sequencing and Consortiums etc.

It is in humankind to believe in magic and illusion.  The strength of biological diversity and complex mechanism of expression may chalanges the set up of a simple but informative specific essay.  Thus, there is a new developing field to mash rules of biology with mathematical formulas to develop the best bioinformatics or also called computational biology.  Predicting transcription start or termination sites, exon boundaries, possible binding sites of transcription regulators for chromatin modification activities, like histone acetylates and enhancer- and insulator-associated factors based on the human genome sequence.  Deep in mind, this assumption supports that the sequence contains signatures for chromatin modifications essential for gene regulation and development.

There are three primary colors, red, yellow and blue, however, an artist can create many shades. Recently, scientists combining and organizing more data to make sense of our blueprint of life to transfer info generation to generation with the hope to cure diseases of human kind.

Analyzing genome and transcriptome open the door.  These studies suggested that all eukaryotic cells has a rich portfolio of RNAs. Among these long non-coding RNAs has impact on protein coding gene expression, regulating multiple processes even including epigenetic gene expression.

Epigenetics, stemness and non-coding RNAs  play a great role to manipulate and correct the gene expression not only at a proper cell type but also location and time within genome without disturbing the host.

Main concern is differentiation of embryonic stem cells under these epigenetics and influencers.  The best known post-transcriptional modifications, which include methylation, acetylation, ubiquination, and SUMOylation of lysine residues, methylation of arginine residues, and phosphorylation of serines, occur on histone tails. “Epi” means “top” or
“above” so this mechanism give a new direction to the genetic pathways as long as the organism live sometime and may lead into evolutions.  It is critical to show the complexity of
mechanism and relativity of a gene role with a single example for each. 

For example,  DNA methylation occurs mostly on cytosine residues on the CpG islands usually located on promoter regions that are associated with tissue-specific gene expression.  However, there are many other forms of DNA methylations, such as  monoallelic methylation in gene imprinting and inactivation of the X chromosome,  in repetitive elements, like transposons.  There are two main mechanisms but this is not our main topic.  Yet, Myc and hypoxia-inducible factor-1α versus certain methyl-CpG-binding proteins, such as MBD1,MBD2, MBD4, MeCP2, and Kaiso works differently.

Stemness is an important factor for an intervention to correct a pathological condition. In terms of epigenetics, regulation and non-coding RNA Vascular endothelial growth factor A (VEGF-A) is an interesting example for differentiation of endothelial cells and morphogenesis of the vascular system during development with several reasons, epigenetics, gene interactions, time and space.  Everything has to be just right, because neither less nor too much can fulfill the destiny to become a complete adult cell or an organism.   For example, both having only one VEGF-A allele and having two-fold excess of VEGF-A results in death during early embryogenesis, since mice can’t develop proper vascular network.  However, explaining diverse mechanisms and functions of VEGF-A is require more information with specific details.  VEGF-A plays many roles in many pathological cases, such as cancer, inflammation, retinopathies, and arthritis because VEGF-A has also function in epigenetic reprogramming of the promoter regions of Rex1 and Oct4 genes, that are critical for a stem cell. Preferred mechanism is anti-angiogeneic state but tumor cells prefer hypermethylation to induce pro-angiogeneic state, thus VEGF-A stimulates PIGF in tumour cells among many other factors.

Now, let’s turn around to observe development of a cell with Polycomb repressive complexes (PRCs) because they are important chromatin regulators of embryonic stem (ES) cell function.  Originally, RYBP shown to function  as transcriptional repressor in reporter assays from both in tissue culture cells and in fruit fly (Drosophila melanogaster ) and as a direct interactor with Ring1A during embryogenesis through methylation. In addition, RYBP in epigenetic resetting during preimplantation development through repression of germ line genes and PcG targets before formation of pluripotent epiblast cells.  However, I do believe that the most important element is efficient repression of endogenous retroviruses (murine endogenous retrovirus called MuERV class),  preimplantation containing zygotic genome activation stage and germ line specific genes. The selective repressor activity of  RYBP  is in the ES cell state. When RYBP−/− ES cells were analyzed by measuring gene expression during differentiation as embryo bodies formed from mutant and wild-type cells, the result presented that  expression of pluripotency genes Oct4 and Nanog was usually downregulated. However, RYBP is able to bind genomic regions independently of H3K27me3 and there is no relation between altered RYBP binding in Dnmt1-mutant cells to DNA methylation status. In sum, RYBP has a large value in undifferentiated ES cells and may affect or even reset epigenetic landscape during early developmental stages. These are the gaps filled by long non coding RNAs.

We learn more compelling information by comparing and contrasting what is normal and what is abnormal. As a result, pathology is a key learning canvas for basic mechanisms in molecular genetics. Then peppered with functional genomics completes the story for an edible outcome.  We generally refer this as a Translational Research.  For example, recent foundlings suggest that H19 contributes to cancer, including hepatocellular carcinoma (HCC) after reviewing Oncomine resource.  According to these observations, in most HCC cases there is a lower expression of  H19 level is compared to the liver. Thus, in vitro and in vivo studies were undertaken with classical genetic analyzes based on loss- and gain-of-function on H19 to characterize two outcomes depend on H19, that are the effects on gene expression and on HCC metastasis. First, the expression of H19 showed gene expression variation since H19 expression was low in tumor cells than peripheral tumor cells.  Second, the metastasis of cancer based on alteration of miR-200 pathway contributing mesenchymal-to-epithelial transition by H19. Therefore, H19 and miR-200 are targets to be utilized during molecular diagnostics development and establishing targeted therapies in cancer.

Long story short, there is a circle of life where everything is connected even though they look different.  As a result, when we see a sunflower or a baby we remember to smile, because life is still an act to puzzle human.

References and Further Readings:

 

Non-coding RNAs as regulators of gene expression and epigenetics” Cardiovascular Res 1 June 2011: 430-440.

Epigenetic regulation of key vascular genes and growth factors” Cardiovasc Res 1 June 2011: 441-446.

Epigenetic Regulation by Long Noncoding RNAs” Science 14 December 2012: 1435-1439.

Epigenetic control of embryonic stem cell fate” JEM 25 October 2010: 2287-2295.

Transcribed dark matter: meaning or myth?” Hum Mol Genet 15 October 2010: R162-R168.

Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma” Carcinogenesis 1 March 2013: 577-586.

Vernalization-Mediated Epigenetic Silencing by a Long Intronic Noncoding RNA” Science 7 January 2011: 76-79.

Predicting the probability of H3K4me3 occupation at a base pair from the genome sequence context” Bioinformatics 1 May 2013: 1199-1205.

 

Further Readings specific to Embryonic Stem Cell Differentiation and Development :

“BMP Induces Cochlin Expression to Facilitate Self-renewal and Suppress Neural Differentiation of Mouse Embryonic Stem Cells” J. Biol. Chem. 2013 288:8053-8060

Abstract

“Regulation of DNA Methylation in Rheumatoid Arthritis Synoviocytes”  J. Immunol. 2013 190:1297-1303

Abstract

“DNA methylome signature in rheumatoid arthritis” Ann Rheum Dis 2013 72:110-117

Abstract

“The histone demethylase Kdm3a is essential to progression through differentiation” Nucleic Acids Res 2012 40:7219-7232

Abstract

“Targeted silencing of the oncogenic transcription factor SOX2 in breast cancer” Nucleic Acids Res 2012 40:6725-6740

Abstract

“Yin Yang 1 extends the Myc-related transcription factors network in embryonic stem cells” Nucleic Acids Res 2012 40:3403-3418

Abstract

“RYBP Represses Endogenous Retroviruses and Preimplantation- and Germ Line-Specific Genes in Mouse Embryonic Stem Cells” Mol. Cell. Biol. 2012 32:1139-1149

Abstract

“Polycomb Repressor Complex-2 Is a Novel Target for Mesothelioma Therapy” Clin. Cancer Res. 2012 18:77-90

Abstract

“OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes” Proc. Natl. Acad. Sci. USA 2011 108:14497-14502

Abstract

“Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging” Blood 2011 117:e182-e189

Abstract

“The CHD3 Chromatin Remodeler PICKLE and Polycomb Group Proteins Antagonistically Regulate Meristem Activity in the Arabidopsis” RootPlant Cell 2011 23:1047-1060

Abstract

“Chromatin structure of pluripotent stem cells and induced pluripotent stem cells” Briefings in Functional Genomics 2011 10:37-49

Abstract

Abbreviations used:

DNMT       DNA methyl transferase

ES             embryonic stem

JmjC         Jumonji C

lincRNA     long ncRNA

ncRNA       noncoding RNA

PcG          Polycomb group

PRC          Polycomb repressive complex

PRE          Polycomb repressive element

Previous Posts on Stem Cells:

…  Aviva Lev-Ari, PhD, RN New Life – The Healing Promise of Stem Cells View … p://www.technioniit.com/2012/09/new-life-healing-promise-of-stem-cells.html       Diseases and conditions where stem cell treatment is promising or emerging. Source: Wikipedia Since the …

…  Aviva Lev-Ari, PhD, RN Stem cells create new heart cells in baby mice, but not in adults, study …  picture on the left shows green c-kit+ precursor stem cells within an infarct (lower right) in a

14 January 2013  by Dr. Sudipta Saha on Pharmaceutical Intelligence
…  and Curator: Dr. Sudipta Saha, Ph.D. Germline stem cells that produce oocytes in vitro and fertilization-competent eggs in …  from adult mouse ovaries. A fluorescence-activated cell sorting-based protocol has been standardized that can be used with adult …  compared to the ESC-derived or induced pluripotent stem cell-derived germline cells that are currently used as models for human …

…  PhD, RN The two leading therapy classes are: Cell-based Therapies for angiogenesis and myocardial …  Research Projects Stem Cell biology Embryonic stem cells in cardiovascular repairEarly differentiation of human endothelial …

…  Stem Cells with Unread Genome: microRNAs Author, Demet Sag, PhD Life is …  a coherent outcome. Thus, providing an engineered whole cell as a system of correction for “Stem Cell Therapy” may resolve unmet health problems.  Only 1% of the genome …

…  are not yet known. Some studies suggest a high rate of stem cell activity with differentiation of progenitors to cardiomyocytes. Other …

…  T-cells, said Dr. Margaret Goodell, director of the Stem Cells and Regenerative Medicine Center of Baylor College of Medicine. …  of pediatrics at BCM and a member of the Center for Cell and Gene Therapy at BCM, Texas Children¹s Hospital and The Methodist …  found that mice lacking the gene for this factor had a T-cell deficiency and in particular, too few of these early progenitor …

28 March 2013  by ritusaxena on Pharmaceutical Intelligence
…  and Curator: Ritu Saxena, Ph.D Although cancer stem cells constitute only a small percentage of the tumor burden, their …  after therapeutic target in cancer. The post on cancer stem cells published on the 22nd of March, 2013, describes the identity of CSCs, their functional characteristics, possible cell of origin and biomarkers. This post focuses on the therapeutic potential …

…  programs in the fields of personalized medicine, cell biology, cytogenetics, genotyping, and biobanking drive our …  by playing an important role in induced pluripotent stem (iPS) cell research. Induced pluripotent stem cells are powerful cells which can be made from skin or blood cells, and …

30 November 2012  by sjwilliamspa on Pharmaceutical Intelligence
…  seen in hematologic malignancies such as cutaneous T-cell lymphoma and peripheral T-cell lymphoma and little or no positive outcome …  resistance to chemotherapeutics, and similarity to cancer stem cells(6-10). Figure 1. HDACis led to the induction of EMT phemotype. (A …

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Reporter: Ritu Saxena, Ph.D.

Diabetes currently affects more than 336 million people worldwide, with healthcare costs by diabetes and its complications of up to $612 million per day in the US alone.  The islets of Langerhans, miniature endocrine organs within the pancreas, are essential regulators of blood glucose homeostasis and play a key role in the pathogenesis of diabetes.  Islets of Langerhans are composed of several types of endocrine cells.  The α- and β-cells are the most abundant and also the most important in that they secrete hormones (glucagon and insulin, respectively) crucial for glucose homeostasis (Bosco D, et al, Diabetes, May 2010;59(5):1202-10).

Diabetes is a ‘bihormonal’ disease, involving both insulin deficiency and excess glucagon.  For decades, insulin deficiency was considered to be the sole reason for diabetes; however, recent studies emphasize excess glucagon as an important part of diabetes etiology.  Thus, insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development.  Increasing the number of insulin-producing β cells while decreasing the number of glucagon-producing α cells, either in vitro in donor pancreatic islets before transplantation into type 1 diabetics or in vivo in type 2 diabetics, is a promising therapeutic avenue.  A huge leap has been taken in this direction by the researchers at the University of Pennsylvania (Philadelphia, PA) in collaboration with Oregon Health and Science University (Portland, OR), USA by demonstrating that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets.  In fact, the treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets.  The research findings were published in the Journal of Clinical Investigation.

Study design: First step was to study and analyze the epigenetic and transcriptional landscape of human pancreatic human pancreatic α, β, and exocrine cells using ChIP and RNA sequencing.  Study design for determination of the transcriptome and differential histone marks included the dispersion and FACS to of human islets to obtain cell populations highly enriched for α, β, and exocrine (duct and acinar) cells.  Then, chromatin was prepared for ChIP analysis using antibodies for histone modifications, H3K4me3 (represents gene activation) and H3K27me3 (represents gene repression).  RNA-Sequencing analysis was then performed to determine mRNA and lncRNA.  Sample purity was confirmed using qRT-PCR of insulin and glucagon expression levels of the individual α and β cell population revealing high sample purity.

Results:

  • Long noncoding transcripts: Long noncoding RNA molecules have been implicated as important developmental regulators, cell lineage allocators, and contributors to disease development.  The authors discovered 12 cell–specific and 5 α cell–specific noncoding (lnc) transcripts, indicative of the valuable research resource represented from transcriptome data.  Recently discovered lncRNA molecules in islets are regulated during development and dysregulated in type 2 diabetic islets.
  • Monovalent histone modification landscapes shared among three cell types:  Monovalent H3K4me3-enriched regions, indicative of gene activation, were identified and compared in α, β, and exocrine cells.  Strikingly, the vast majority of monovalently H3K4me3-marked genes were shared among the 3 pancreatic cell lineages (83%–95%), reflecting both their related function in protein secretion and common embryonic descent. Similarly, a high degree of overlap was observed in H3K27me3 modification patterns in all the three cell types (73%–83%).
  • Bivalent histone modifications (H3K4me3 and H3K27me3) were high in α cells: Bernstein colleagues observed bivalent marks to be common in undifferentiated cells, such as ES cells and pluripotent progenitor cells, and in most cases, one of the histone modification marks was lost during differentiation, accompanying lineage specification (Bernstein BE, et al, Cell, 21 Apr 2006; 125(2):315-26).  α cells exhibited many more genes bivalently marked, followed by β cells and exocrine cells.  Bivalent state was remarkably similar to that of hESC, suggesting a more plastic epigenomic state for α cells.
  • Monovalent histone modifications were high in β cells: Thousands of the genes that were in bivalent state in α cells were in a monovalent state, carrying only the activating or repressing mark.
  • Inhibition of histone methyltransferases led to partial cell-fate conversion: Adenosine dialdehye (Adox), a drug that interferes with histone methylation and decreases H3K27me3, when administered in human islet tissue, led to decrease of H3K27me3 enrichment at the 3 gene loci that are originally expressed bivalently in α cells and monovalently in β cells:  MAFA, PDX1 and ARX.  Adox resulted in the occasional cooccurrence of glucagon and insulin granules within the same islet cell, which was not observed in untreated islets.  Thus, inhibition of histone methyltransferases leads to partial endocrine cell-fate conversion.

Conclusion:  α cells have been reprogrammed into β cell fate in various mouse models.  The reason, as proposed by the authors, might be the presence of more bivalently marked genes that confers a more plastic epigenomic state of the cells that probably drives them to the β cell fate.  Therefore, using epigenomic information of different cell types in pancreatic islets and harnessing it for subsequent manipulation of their epigenetic signature could be utilized to reprogram cells and hence provide a path for diabetes therapy.

Source: Bramswig NC, et al, Epigenomic plasticity enables human pancreatic α to β cell reprogramming. J Clin Invest, 22 Feb 2013. pii: 66514.

Related reading on Pharmaceutical Intelligence:

Junk DNA codes for valuable miRNAs: non-coding DNA controls Diabetes

Therapeutic Targets for Diabetes and Related Metabolic Disorders

Reprogramming cell fate

CRACKING THE CODE OF HUMAN LIFE: Recent Advances in Genomic Analysis and Disease – Part IIC

2013 Genomics: The Era Beyond the Sequencing of the Human Genome: Francis Collins, Craig Venter, Eric Lander, et al.

Genome-Wide Detection of Single-Nucleotide and Copy-Number Variation of a Single Human Cell

SNAP: Predict Effect of Non-synonymous Polymorphisms: How well Genome Interpretation Tools could Translate to the Clinic

Genomic Endocrinology and its Future

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