Cohesin organizes 3D DNA contacts surrounding active enhancers inC. elegans

Abstract

In mammals, cohesin and CTCF organize the 3D genome into topologically associated domains (TADs) to regulate communication between cis-regulatory elements. However, many organisms, including S. cerevisiae, C. elegans, and A. thaliana lack CTCF. Here, we use C. elegans as a model to investigate the function of cohesin in 3D genome organization in an animal without CTCF. We use auxin-inducible degradation to acutely deplete SMC-3 or its negative regulator WAPL-1 from somatic cells. Using Hi-C data, we identify a cohesin-dependent 3D genome feature termed chromatin jets (aka fountains), also observed in zebrafish and mammalian genomes. The jets emerge from NIPBL occupied segments, and the trajectory of the jets coincides with cohesin binding. The spreading of cohesin from jet origins depends on a fully intact cohesin complex and is extended upon WAPL-1 depletion. These results support the idea that cohesin is preferentially loaded at NIPBL occupied sites, from which cohesin loop extrudes in an effectively two-sided manner. The location of putative loading sites coincides with active enhancers and the pattern of chromatin jets correlates with transcription. We propose that in the absence of CTCF, preferential loading of cohesin at enhancers is a conserved mechanism of genome organization that regulates the interaction of gene regulatory elements in 3D.

The jet-like chromatin structure defines active secondary metabolism in fungi

“…graminearum . Chromatin jets and analogous structures, such as plumes, fountains and ‘hinge-like’ domains, have been observed in mammals ( 52 , 81 ), worms ( 82 , 83 ) and zebrafish ( 84 , 85 ). There is evidence suggesting that these structures arise from specific cohesin loading in narrow accessible chromatin regions ( 52 ).…”

“…There is evidence suggesting that these structures arise from specific cohesin loading in narrow accessible chromatin regions ( 52 ). While CTCF (CCCTC-binding factor), a blocker of cohesin, is not necessary for jet formation, it can impact cohesin looping and thus shape the domain structure ( 52 , 83 ). Consistently, genomes with or without CTCF proteins exhibit jet-like chromatin structures.…”

“…The precise mechanisms driving preferential cohesin loading remain unclear. Emerging studies indicate that this targeted loading occurs at enhancers, and the absence of certain pioneer transcription factors, which establish open chromatin regions and facilitate H3K27 acetylation on enhancers, can influence the formation of the jet-like domain ( 83 ). Moreover, H3K27ac-associated BET proteins interact with cohesin motors, and thus can affect the loading of cohesin ( 86 , 87 ).…”

Cohesin chromatin loop formation by an extrinsic motor

“…While the molecular nature of cohesin's transcriptiondependent loop substrate remains to be further explored, chromatin contact stripes along active mouse genes are suggestive of cohesin-mediated interactions between open promoter elements and the moving transcription machinery 58 . Such stripes are exemplified in nematodes in the form of 'jets' that stretch out from cohesin loader binding sites along active genes 63 . If cohesin is stable enough, e.g.…”

Unique territorial and compartmental organization of chromosomes in the holocentric silkmoth

“…In C. elegans, specific sequences direct the SMC-containing dosage compensation complex to 36,80 . Most recently, targeted loading of SMCs has been reported at enhancers in C. elegans 11,81 and in vertebrates 10,12,82 . Such targeted loading in these systems may be guided by differences in DNA accessibility, sequence-specific DNA binding proteins 77,78 , or via specific histone marks 10,12,82 .…”