Epigenetic modulation of cell fate during pancreas development

Abstract

Epigenetic modifications to DNA and its associated proteins affect cell plasticity and cell fate restrictions throughout embryonic development. Development of the vertebrate pancreas is characterized by initial is an over-lapping expression of a set of transcriptional regulators in a defined region of the posterior foregut endoderm that collectively promote pancreas progenitor specification and proliferation. As development progresses, these transcription factors segregate into distinct pancreatic lineages, with some being maintained in specific subsets of terminally differentiated pancreas cell types throughout adulthood. Here we describe the progressive stages and cell fate restrictions that occur during pancreas development and the relevant known epigenetic regulatory events that drive the dynamic expression patterns of transcription factors that regulate pancreas development. In addition, we highlight how changes in epigenetic marks can affect susceptibility to pancreas diseases (such as diabetes), adult pancreas cell plasticity, and the ability to derive replacement insulin-producing β cells for the treatment of diabetes.

Keywords: diabetes; epigenetics; pancreas development; β cell.

Figure 1.. Comparison of pancreatic cell development across model systems.

All pancreatic epithelial lineages arise from the foregut endoderm. Distinct expression of key transcription factors (shown as + or −) driving cells towards a specific pancreatic cell stage or fate are listed between each cell type. Solid black arrows indicate known cell transitions; dotted arrows represent hypothesized intermediate cell populations; question marks indicate transcription factors that have yet to be characterized. While most of the developmental stages and transcription factors are conserved between mouse and human pancreas organogenesis, there are differences in the relative time points at which each cell type arises and the length of time they persist. The different colored arrows represent the corresponding cell type and how long they persist within the pancreas throughout development. Created with Biorender.com.

Figure 2.. Epigenetic programming during endocrine lineage specification.

(A) Pancreas developmental stages are specifically affected by different epigenetic modifications (and their enzyme catalysts) such as DNA methylation (DNMT), histone methylation (EZH2), and histone deacetylation (HDAC). (B) Histone PTMs: Histone methyl transferases (HMTs) add methyl groups, which can inhibit gene transcription; demethylases (JMJD3) reverse histone methylation. Histone acetyl transferases (HATs) add acetyl groups to histones leading to increased transcription; histone deacetylases (HDACs) remove acetylation marks. (C) DNMTs add methyl groups to mainly cytosine bases in DNA at the promoter region, inhibiting transcription; TET enzymes remove methyl groups, leading to derepression. (D) Long noncoding RNAs (lncRNAs) regulate transcription through epigenetic modification by acting on 1. RNA Polymerase (Pol) II; 2. binding to gene promoters or 3. enhancers, or 4. binding to transcription regulator complexes. Created with Biorender.com.

Figure 3.. Working models for Pdx1 and Oc1 cooperative function in β cell development.

Top row: In normal development, Pdx1 and Oc1 cooperate to promote endocrine development in two potential ways: 1. Direct: By binding to and activating promoters of downstream transcriptional regulators in MPCs (left) that promote endocrine development (represented by different colored transcripts). In terminally differentiated β cells (right), those downstream transcriptional regulators (colored ovals) activate expression of functional genes (represented by black transcripts); 2. Indirect: In MPCs (left) Pdx1 and Oc1 establish a permissive epigenetic environment by adding activating histone modifications (green symbols) to existing repressive histone modifications (red symbols) at key endocrine genes. This poised, permissive epigenetic environment allows for later expression of functional genes in differentiated β cells (right). Bottom row: In the context of Pdx1/Oc1 double heterozygosity, reduced levels of Pdx1 and Oc1 result in: 1. Reduced expression in MPCs (left) of downstream transcription factors required for endocrine differentiation and thus reduced expression of functional genes in differentiated β cells (right); 2. Lower levels of Pdx1 and Oc1 prevent the establishment of a permissive epigenetic landscape at functional genes in MPCs (left), resulting in inaccessibility of these promoters later in differentiated β cells (right). Created with Biorender.com.