Postmitotic differentiation of human monocytes requires cohesin-structured chromatin

Julia Minderjahn, Alexander Fischer, Konstantin Maier, Karina Mendes, Margit Nuetzel, Johanna Raithel, Hanna Stanewsky, Ute Ackermann, Robert Månsson, Claudia Gebhard, Michael Rehli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cohesin is a major structural component of mammalian genomes and is required to maintain loop structures. While acute depletion in short-term culture models suggests a limited importance of cohesin for steady-state transcriptional circuits, long-term studies are hampered by essential functions of cohesin during replication. Here, we study genome architecture in a postmitotic differentiation setting, the differentiation of human blood monocytes (MO). We profile and compare epigenetic, transcriptome and 3D conformation landscapes during MO differentiation (either into dendritic cells or macrophages) across the genome and detect numerous architectural changes, ranging from higher level compartments down to chromatin loops. Changes in loop structures correlate with cohesin-binding, as well as epigenetic and transcriptional changes during differentiation. Functional studies show that the siRNA-mediated depletion of cohesin (and to a lesser extent also CTCF) markedly disturbs loop structures and dysregulates genes and enhancers that are primarily regulated during normal MO differentiation. In addition, gene activation programs in cohesin-depleted MO-derived macrophages are disturbed. Our findings implicate an essential function of cohesin in controlling long-term, differentiation- and activation-associated gene expression programs.
Original languageEnglish
Article number4301
Number of pages19
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - Dec 2022

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