Tissue-specific Grb10/Ddc insulator drives allelic architecture for cardiac development
Copyright © 2022 Elsevier Inc. All rights reserved..
Allele-specific expression of imprinted gene clusters is governed by gametic DNA methylation at master regulators called imprinting control regions (ICRs). Non-gametic or secondary differentially methylated regions (DMRs) at promoters and exonic regions reinforce monoallelic expression but do not control an entire cluster. Here, we unveil an unconventional secondary DMR that is indispensable for tissue-specific imprinting of two previously unlinked genes, Grb10 and Ddc. Using polymorphic mice, we mapped an intronic secondary DMR at Grb10 with paternal-specific CTCF binding (CBR2.3) that forms contacts with Ddc. Deletion of paternal CBR2.3 removed a critical insulator, resulting in substantial shifting of chromatin looping and ectopic enhancer-promoter contacts. Destabilized gene architecture precipitated abnormal Grb10-Ddc expression with developmental consequences in the heart and muscle. Thus, we redefine the Grb10-Ddc imprinting domain by uncovering an unconventional intronic secondary DMR that functions as an insulator to instruct the tissue-specific, monoallelic expression of multiple genes-a feature previously ICR exclusive.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:82 |
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| Enthalten in: |
Molecular cell - 82(2022), 19 vom: 06. Okt., Seite 3613-3631.e7 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Juan, Aimee M [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.10.2022 Date Revised 07.10.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.molcel.2022.08.021 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Tissue-specific Grb10/Ddc insulator drives allelic architecture for cardiac development |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 Elsevier Inc. All rights reserved. | ||
| 520 | |a Allele-specific expression of imprinted gene clusters is governed by gametic DNA methylation at master regulators called imprinting control regions (ICRs). Non-gametic or secondary differentially methylated regions (DMRs) at promoters and exonic regions reinforce monoallelic expression but do not control an entire cluster. Here, we unveil an unconventional secondary DMR that is indispensable for tissue-specific imprinting of two previously unlinked genes, Grb10 and Ddc. Using polymorphic mice, we mapped an intronic secondary DMR at Grb10 with paternal-specific CTCF binding (CBR2.3) that forms contacts with Ddc. Deletion of paternal CBR2.3 removed a critical insulator, resulting in substantial shifting of chromatin looping and ectopic enhancer-promoter contacts. Destabilized gene architecture precipitated abnormal Grb10-Ddc expression with developmental consequences in the heart and muscle. Thus, we redefine the Grb10-Ddc imprinting domain by uncovering an unconventional intronic secondary DMR that functions as an insulator to instruct the tissue-specific, monoallelic expression of multiple genes-a feature previously ICR exclusive | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a CTCF insulators | |
| 650 | 4 | |a chromatin organization | |
| 650 | 4 | |a differentiallymethylated regions | |
| 650 | 4 | |a genomic imprinting | |
| 650 | 4 | |a tissue-specific enhancers | |
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| 650 | 7 | |a Grb10 protein, mouse |2 NLM | |
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| 700 | 1 | |a Foong, Yee Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Thorvaldsen, Joanne L |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Yemin |e verfasserin |4 aut | |
| 700 | 1 | |a Leu, Nicolae A |e verfasserin |4 aut | |
| 700 | 1 | |a Rurik, Joel G |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Krapp, Christopher |e verfasserin |4 aut | |
| 700 | 1 | |a Rosier, Casey L |e verfasserin |4 aut | |
| 700 | 1 | |a Epstein, Jonathan A |e verfasserin |4 aut | |
| 700 | 1 | |a Bartolomei, Marisa S |e verfasserin |4 aut | |
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