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Allelic chromatin structure precedes imprinted expression of Kcnk9 during neurogenesis.

Authors
  • Loftus, Daniel1
  • Bae, Bongmin1
  • Whilden, Courtney M1
  • Whipple, Amanda J2
  • 1 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
  • 2 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA [email protected].
Type
Published Article
Journal
Genes & development
Publication Date
Sep 01, 2023
Volume
37
Issue
17-18
Pages
829–843
Identifiers
DOI: 10.1101/gad.350896.123
PMID: 37821107
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Differences in chromatin state inherited from the parental gametes influence the regulation of maternal and paternal alleles in offspring. This phenomenon, known as genomic imprinting, results in genes preferentially transcribed from one parental allele. While local epigenetic factors such as DNA methylation are known to be important for the establishment of imprinted gene expression, less is known about the mechanisms by which differentially methylated regions (DMRs) lead to differences in allelic expression across broad stretches of chromatin. Allele-specific higher-order chromatin structure has been observed at multiple imprinted loci, consistent with the observation of allelic binding of the chromatin-organizing factor CTCF at multiple DMRs. However, whether allelic chromatin structure impacts allelic gene expression is not known for most imprinted loci. Here we characterize the mechanisms underlying brain-specific imprinted expression of the Peg13-Kcnk9 locus, an imprinted region associated with intellectual disability. We performed region capture Hi-C on mouse brains from reciprocal hybrid crosses and found imprinted higher-order chromatin structure caused by the allelic binding of CTCF to the Peg13 DMR. Using an in vitro neuron differentiation system, we showed that imprinted chromatin structure precedes imprinted expression at the locus. Additionally, activation of a distal enhancer induced imprinted expression of Kcnk9 in an allelic chromatin structure-dependent manner. This work provides a high-resolution map of imprinted chromatin structure and demonstrates that chromatin state established in early development can promote imprinted expression upon differentiation. © 2023 Loftus et al.; Published by Cold Spring Harbor Laboratory Press.

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