Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma

Deforzh, Evgeny; Uhlmann, Erik J.; Das, Eashita; Galitsyna, Aleksandra A.; Arora, Ramil; Saravanan, Harini; Rabinovsky, Rosalia; Wirawan, Aditya; Teplyuk, Nadiya M.; Fatimy, Rachid El; Perumalla, Sucika; Jairam, Anirudh; Wei, Zhiyun; Mirny, Leonid A.; Krichevsky, Anna M.

doi:10.1016/j.molcel.2022.03.018

Cited by 21 publications

(21 citation statements)

References 83 publications

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“…For instance, histone marks or transcription factors could regulate genomic contacts by locally activating transcription, thus modulating functional interactions in cis via extrusion. Similarly, even non-protein-coding genes could have this effect through, for example, transcription of noncoding RNAs and eRNAs ( 96 , 97 ). Thus, while cohesin may only moderately alter global transcription ( 6 , 8 – 11 , 98 ), cohesin–RNAP interactions could impact transcription of specific genes that depend on the recruitment of nearby cis regulatory elements.…”

Section: Resultsmentioning

confidence: 99%

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Banigan

Tang

Berg

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Cohesin folds mammalian interphase chromosomes by extruding the chromatin fiber into numerous loops. “Loop extrusion” can be impeded by chromatin-bound factors, such as CTCF, which generates characteristic and functional chromatin organization patterns. It has been proposed that transcription relocalizes or interferes with cohesin and that active promoters are cohesin loading sites. However, the effects of transcription on cohesin have not been reconciled with observations of active extrusion by cohesin. To determine how transcription modulates extrusion, we studied mouse cells in which we could alter cohesin abundance, dynamics, and localization by genetic “knockouts” of the cohesin regulators CTCF and Wapl. Through Hi-C experiments, we discovered intricate, cohesin-dependent contact patterns near active genes. Chromatin organization around active genes exhibited hallmarks of interactions between transcribing RNA polymerases (RNAPs) and extruding cohesins. These observations could be reproduced by polymer simulations in which RNAPs were moving barriers to extrusion that obstructed, slowed, and pushed cohesins. The simulations predicted that preferential loading of cohesin at promoters is inconsistent with our experimental data. Additional ChIP-seq experiments showed that the putative cohesin loader Nipbl is not predominantly enriched at promoters. Therefore, we propose that cohesin is not preferentially loaded at promoters and that the barrier function of RNAP accounts for cohesin accumulation at active promoters. Altogether, we find that RNAP is an extrusion barrier that is not stationary, but rather, translocates and relocalizes cohesin. Loop extrusion and transcription might interact to dynamically generate and maintain gene interactions with regulatory elements and shape functional genomic organization.

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Section: Resultsmentioning

confidence: 99%

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Banigan

Tang

Berg

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…For instance, histone marks or transcription factors could regulate genomic contacts by locally activating transcription, thus modulating functional interactions in cis via extrusion. Similarly, even non-protein-coding genes could have this effect through, for example, transcription of non-coding RNAs and eRNAs (96,97). Thus, while cohesin may only moderately alter global transcription (6,(8)(9)(10)(11)98), cohesin-RNAP interactions could impact transcription of specific genes that depend on the recruitment of nearby cis regulatory elements.…”

Section: Discussionmentioning

confidence: 99%

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Banigan

Tang

Berg

et al. 2022

Preprint

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Cohesin organizes mammalian interphase chromosomes by reeling chromatin fibers into dynamic loops (Banigan and Mirny, 2020; Davidson et al., 2019; Kim et al., 2019; Yatskevich et al., 2019). "Loop extrusion" is obstructed when cohesin encounters a properly oriented CTCF protein (Busslinger et al., 2017; de Wit et al., 2015; Fudenberg et al., 2016; Nora et al., 2017; Sanborn et al., 2015; Wutz et al., 2017), and recent work indicates that other factors, such as the replicative helicase MCM (Dequeker et al., 2020), can also act as barriers to loop extrusion. It has been proposed that transcription relocalizes (Busslinger et al., 2017; Glynn et al., 2004; Lengronne et al., 2004) or interferes with cohesin (Heinz et al., 2018; Jeppsson et al., 2020; Valton et al., 2021; S. Zhang et al., 2021), and that active transcription start sites function as cohesin loading sites (Busslinger et al., 2017; Kagey et al., 2010; Zhu et al., 2021; Zuin et al., 2014), but how these effects, and transcription in general, shape chromatin is unknown. To determine whether transcription can modulate loop extrusion, we studied cells in which the primary extrusion barriers could be removed by CTCF depletion and cohesin's residence time and abundance on chromatin could be increased by Wapl knockout. We found evidence that transcription directly interacts with loop extrusion through a novel "moving barrier" mechanism, but not by loading cohesin at active promoters. Hi-C experiments showed intricate, cohesin-dependent genomic contact patterns near actively transcribed genes, and in CTCF-Wapl double knockout (DKO) cells (Busslinger et al., 2017), genomic contacts were enriched between sites of transcription-driven cohesin localization ("cohesin islands"). Similar patterns also emerged in polymer simulations in which transcribing RNA polymerases (RNAPs) acted as "moving barriers" by impeding, slowing, or pushing loop-extruding cohesins. The model predicts that cohesin does not load preferentially at promoters and instead accumulates at TSSs due to the barrier function of RNAPs. We tested this prediction by new ChIP-seq experiments, which revealed that the "cohesin loader" Nipbl (Ciosk et al., 2000) co-localizes with cohesin, but, unlike in previous reports (Busslinger et al., 2017; Kagey et al., 2010; Zhu et al., 2021; Zuin et al., 2014), Nipbl did not accumulate at active promoters. We propose that RNAP acts as a new type of barrier to loop extrusion that, unlike CTCF, is not stationary in its precise genomic position, but is itself dynamically translocating and relocalizes cohesin along DNA. In this way, loop extrusion could enable translocating RNAPs to maintain contacts with distal regulatory elements, allowing transcriptional activity to shape genomic functional organization.

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“…HOX epigenetic priming might also be deleterious, given the role of abnormal HOX expression in tumorigenesis. Within the active TAD of the HOXD cluster, we also observed a contact between HOXD3 and LINC01116 , which also contains an enhancer, which when activated induces hyper-proliferation of astrocytes in culture 82 ( Extended Figure 9e,f ), a glioma-like phenotype 82 . Along with the 3D contact seen in the cultured OPCs, the spinal cord OLGs also displayed increased ATAC and H3K27ac signal at the LINC01116 locus.…”

Section: Discussionmentioning

confidence: 73%

Single-nuclei histone modification profiling of the adult human central nervous system unveils epigenetic memory of developmental programs

Kabbe,

Agirre,

Carlström

et al. 2024

Preprint

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The adult human central nervous system (CNS) is remarkably complex, with neural cells displaying extensive transcriptional heterogeneity. However, how different layers of epigenetic regulation underpin this heterogeneity is poorly understood. Here, we profile the adult human CNS from distinct regions, for chromatin accessibility at the single-nuclei level. In addition, we simultaneously co-profiled the histone modifications H3K27me3 and H3K27ac at the single nuclei-level, providing their first map in all major human CNS cell types. We unveil primed chromatin signatures at HOX loci in spinal cord-derived human oligodendroglia (OLG) but not microglia. These signatures were reminiscent of developmental OLG but were decoupled from robust gene expression. Moreover, using high-resolution Micro-C, we show that induced pluripotent stem cell (iPS) derived human OLGs exhibit a HOX chromatin architecture compatible with the primed chromatin in adult OLGs, and bears a strong resemblance not only to OLG developmental architecture, but also high-grade pontine gliomas. Thus, adult OLG retain epigenetic memory from developmental states, which might enable them to promptly transcribe Hox genes, in contexts of regeneration, but also make them susceptible to gliomagenesis.

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Promoter and enhancer RNAs regulate chromatin reorganization and activation of miR-10b/HOXD locus, and neoplastic transformation in glioma

Cited by 21 publications

References 83 publications

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Transcription shapes 3D chromatin organization by interacting with loop extrusion

Single-nuclei histone modification profiling of the adult human central nervous system unveils epigenetic memory of developmental programs

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