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Intronic elements associated with insomnia and restless legs syndrome exhibit cell type-specific epigenetic features contributing to MEIS1 regulation.

Hum. Mol. Genet. 31, 1733-1746 (2021)
Open Access Green: Postprint online available 01/2023
A highly evolutionarily conserved MEIS1 intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation, and eQTLs in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. CRISPR interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS.
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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Quellenangaben Volume: 31, Issue: 11, Pages: 1733-1746 Article Number: , Supplement: ,
Publisher Oxford University Press
Reviewing status Peer reviewed