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Islet Epigenetic Impacts on β‐Cell Identity and Function

Maria L. Golson

10.1002/cphy.c200004

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

The development and maintenance of differentiation is vital to the function of mature cells. Terminal differentiation is achieved by locking in the expression of genes essential for the function of those cells. Gene expression and its memory through generations of cell division is controlled by transcription factors and a host of epigenetic marks. In type 2 diabetes, β cells have altered gene expression compared to controls, accompanied by altered chromatin marks. Mutations, diet, and environment can all disrupt the implementation and preservation of the distinctive β‐cell transcriptional signature. Understanding of the full complement of genomic control in β cells is still nascent. This article describes the known effects of histone marks and variants, DNA methylation, how they are regulated in the β cell, and how they affect cell‐fate specification, maintenance, and lineage propagation. © 2021 American Physiological Society. Compr Physiol 11:1961‐1978, 2021.

Figure 1. Figure 1. This figure illustrates the known epigenetic modifiers that influence the transcription factor cascade governing differentiation and maintenance of the major pancreatic endocrine cell types. To this point, investigation has focused on the β cell.
Figure 2. Figure 2. This figure illustrates how CpG methylation can be inherited or passively lost through cell division. Newly synthesized DNA strands are made without methylation, but maintenance methyltransferases recognize the modification on the original strand and place a methyl group on the complementary cytosine on the new strand. In some cases, especially in aging, the newly replicated strand does not receive CpG methylation at some loci. Subsequent divisions result in a reduced percentage of cells with methylated DNA at the locus in question.
Figure 3. Figure 3. This figure illustrates genomic imprinting at the CDKNIC/KCN1Q loci. In this case, both imprinted genes are normally expressed from the maternal allele. On the maternal allele, an ICR upstream of KCN1Q is unmethylated on the maternal allele, which allows a distal enhancer to loop around to the promoters of both CDKN1C and KCN1Q. The ICR of the paternal allele is methylated, which allows the binding of the insulator protein CTCF, thereby preventing access of the enhancer to the promoters of these two genes. Modified, with permission, from Stampone E, et al., 2018 163.
Figure 4. Figure 4. This figure illustrates how topologically associated domains (TADs) restrict interactions between certain chromatin territories. The ring‐shaped protein complex cohesin and the zinc finger protein CTCF work together to loop chromatin domains and insulate them from other open chromatin, thereby decreasing contact between promoters and enhancers across TADs and encouraging them within TADs. Modified, with permission, from Ghirlando R and Felsenfeld G, 2016 71.


Figure 1. This figure illustrates the known epigenetic modifiers that influence the transcription factor cascade governing differentiation and maintenance of the major pancreatic endocrine cell types. To this point, investigation has focused on the β cell.


Figure 2. This figure illustrates how CpG methylation can be inherited or passively lost through cell division. Newly synthesized DNA strands are made without methylation, but maintenance methyltransferases recognize the modification on the original strand and place a methyl group on the complementary cytosine on the new strand. In some cases, especially in aging, the newly replicated strand does not receive CpG methylation at some loci. Subsequent divisions result in a reduced percentage of cells with methylated DNA at the locus in question.


Figure 3. This figure illustrates genomic imprinting at the CDKNIC/KCN1Q loci. In this case, both imprinted genes are normally expressed from the maternal allele. On the maternal allele, an ICR upstream of KCN1Q is unmethylated on the maternal allele, which allows a distal enhancer to loop around to the promoters of both CDKN1C and KCN1Q. The ICR of the paternal allele is methylated, which allows the binding of the insulator protein CTCF, thereby preventing access of the enhancer to the promoters of these two genes. Modified, with permission, from Stampone E, et al., 2018 163.


Figure 4. This figure illustrates how topologically associated domains (TADs) restrict interactions between certain chromatin territories. The ring‐shaped protein complex cohesin and the zinc finger protein CTCF work together to loop chromatin domains and insulate them from other open chromatin, thereby decreasing contact between promoters and enhancers across TADs and encouraging them within TADs. Modified, with permission, from Ghirlando R and Felsenfeld G, 2016 71.
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Article Title: Islet Epigenetic Impacts on β‐Cell Identity and Function
 

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Maria L. Golson. Islet Epigenetic Impacts on β‐Cell Identity and Function. Compr Physiol 2021, 11: 1961-1978. doi: 10.1002/cphy.c200004