Epigenetics in formation, function, and failure of the endocrine pancreas

Abstract

Background: Epigenetics, in the broadest sense, governs all aspects of the life of any multicellular organism, as it controls how differentiated cells arrive at their unique phenotype during development and differentiation, despite having a uniform (with some exceptions such as T-cells and germ cells) genetic make-up. The endocrine pancreas is no exception. Transcriptional regulators and epigenetic modifiers shape the differentiation of the five major endocrine cell types from their common precursor in the fetal pancreatic bud. Beyond their role in cell differentiation, interactions of the organism with the environment are also often encoded into permanent or semi-permanent epigenetic marks and affect cellular behavior and organismal health. Epigenetics is defined as any heritable - at least through one mitotic cell division - change in phenotype or trait that is not the result of a change in genomic DNA sequence, and it forms the basis that mediates the environmental impact on diabetes susceptibility and islet function.

Scope of review: We will summarize the impact of epigenetic regulation on islet cell development, maturation, function, and pathophysiology. We will briefly recapitulate the major epigenetic marks and their relationship to gene activity, and outline novel strategies to employ targeted epigenetic modifications as a tool to improve islet cell function.

Major conclusions: The improved understanding of the epigenetic underpinnings of islet cell differentiation, function and breakdown, as well as the development of innovative tools for their manipulation, is key to islet cell biology and the discovery of novel approaches to therapies for islet cell failure.

Keywords: DNA methylation; Endocrine pancreas; Epigenetics; Histone marks; Islet cells.

Figure 1

5mC oxidation and demethylation process. 5′-methyl cytosine (5mC) is generated by the action of DNA methyltransferases (DNMTs), and can be oxidized by TET enzymes to produce 5hmC, 5fC, and 5caC. All oxidative derivatives can be diluted out during replication, due to lack of recognition by the DNMT1 (passive demethylation). Alternatively, 5fC and 5caC can be excised by TDG and repaired by the base excision repair mechanism to C (active demethylation).

Figure 2

lncRNAs epigenetically regulate gene transcription through multiple mechanisms. (A) lncRNAs can directly or indirectly bind enhancers and recruit transcription factors to promote chromatin looping and gene activation. (B) lncRNAs can directly or indirectly bind enhancers to block chromatin looping, resulting in gene silencing. (C) lncRNAs can directly or indirectly interact with chromatin while recruiting HATs, HDACs or other chromatin-modifying enzymes to activate or silence gene transcription.

Figure 3

Epigenetic inheritance can be multigenerational or transgenerational. A) Multigenerational inheritance refers to a change in a trait or phenotype in the F1 offspring of males or non-pregnant females (F0) exposed to a stimulus that impacts the epigenome without changing the DNA sequence. B) In the case of a pregnant female exposed to an environmental toxin, for instance, the F0 parent, the F1 fetus, and the F2 germline within the fetus are all exposed. Therefore, in this case, only if the F3 generation also shows an epigenetically altered phenotype does transgenerational inheritance occur.