Postmitotic differentiation of human monocytes requires cohesin-structured chromatin

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.

Hi-C, a chromatin 3D structure technique advancing the functional genomics of immune cells

“…Correspondingly, the expression levels of genes within these TADs decrease, such as the PTGS2 gene, chemokine genes (CXCL1, CXCL2, and CXCL3), and chemokine receptor genes (CCR2, CCR7, and CX3R1) (Zhang et al, 2020b). Furthermore, during the differentiation process, there is an increase in TAD boundary insulation and enhanced interactions within TADs (Minderjahn et al, 2022). Moreover, in differentiated macrophages, low-affinity CTCF is removed from the chromatin loops, while high-affinity CTCF is retained, leading to an increase in chromatin loop strength.…”

Repair of DNA double-strand breaks leaves heritable impairment to genome function

“…On one hand, depletion of topological insulators only causes mild gene deregulation (6, 7). On the other hand, mounting evidence indicates that specific gene regulation upon cellular stimulation (8)(9)(10)(11), differentiation (12)(13)(14)(15)(16)(17)(18)(19), oncogenic transformation (12,(20)(21)(22) or during evolution can be modulated by local topology modifications capable of aligning, disrupting or even re-programming promoter-enhancer interactions and accommodating regulatory factors . Thus, rather than a static picture of 'predetermined' 3-D chromatin context for gene expression, a much more dynamic model is emerging where the topological plasticity of the genome is strategically leveraged when cells need to quickly adapt to a new environment or respond to stimuli including various stress assaults.…”