HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types

Zirkel, Anne; Nikolić, Miloš; Sofiadis, Konstantinos; Mallm, Jan‐Philipp; Brackley, Chris A.; Gothe, Henrike Johanna; Drechsel, Oliver; Becker, Christian; Altmüller, Janine; Josipović, Nataša; Georgomanolis, Theodore; Brant, Lilija; Franzen, Julia; Koker, Mirjam; Gusmao, Eduardo Gade; Costa, Ivan G.; Ullrich, Roland T.; Wagner, Wolfgang; Roukos, Vassilis; Nürnberg, Peter; Marenduzzo, Davide; Rippe, Karsten; Papantonis, Argyris

doi:10.1016/j.molcel.2018.03.030

Cited by 185 publications

(270 citation statements)

References 72 publications

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“…In situ Hi-C data from SA1-/SA2-AID HTC116 cells were generated as described previously (Zirkel et al 2018) in two biological replicates each. Resulting DNA libraries were paired-end sequenced to ~300 million read pairs each on a HiSeq4000 platform (Illumina).…”

Section: Hi-c Sample Preparation Sequencing and Data Analysismentioning

confidence: 99%

“…Compartment analysis was performed using the first principal component of the Hi-C matrices as described ) and TAD boundaries were identified using default setting in (Kruse et al 2016). Binarization and matrix subtractions were performed as previously described (Zirkel et al 2018) and custom scripts are available on request. For plotting insulation heatmaps and averaged loop profiles, normalized interactions values in the twenty 10-kbp bins around each SA1 or SA2 peak were added up, normalized to the median value in each matrix and plotted provided the local maxima are higher than the third quantile of all Hi-C data in the matrix.…”

Section: Hi-c Sample Preparation Sequencing and Data Analysismentioning

confidence: 99%

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Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

Casa¹,

Gines²,

Gusmao

et al. 2019

Preprint

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Cohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, SA1 or SA2. How these variable subunits affect the function of the cohesin complex is still unclear. SA1-and SA2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of SA1 and SA2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either SA1 or SA2. Following rapid depletion of either subunit, we perform high resolution Hi-C, RNA-sequencing and sequential ChIP studies to show that SA1 and SA2 do not co-occupy individual binding sites and have distinct ways how they affect looping and gene expression. These findings are supported at the single cell level by single-molecule localizations via dSTORM super-resolution imaging. Since somatic and congenital mutations of the SA subunits are associated with cancer (SA2) and intellectual disability syndromes with congenital abnormalities (SA1 and SA2), we verified SA1-/SA2-dependencies using human neural stem cells, hence highlighting their importance for understanding particular disease contexts.

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Section: Hi-c Sample Preparation Sequencing and Data Analysismentioning

confidence: 99%

Section: Hi-c Sample Preparation Sequencing and Data Analysismentioning

confidence: 99%

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

Casa¹,

Gines²,

Gusmao

et al. 2019

Preprint

Self Cite

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“…We generated stable doxycycline-inducible iPSCs overexpressing equal levels of HA-tagged wt and mut-CHD6 via random genomic integrations of each ORF using a piggybac vector (as in ref. 37; Fig. 4c).…”

Section: Mutated Chd6 Fails To Recruit Co-factors and Activate Autophmentioning

confidence: 90%

“…3k,l). Finally, we could detect hallmarks of a senescence-like phenotype in cells carrying mutant CHD6 alleles, most likely due to damage accumulation 36,37 . The presence of mutCHD6 coincided with reduced levels of H3K27me3-marked heterochromatin ( Fig.…”

Section: Chd6 Mutation Leads To Impaired Autophagy and Increased Dna mentioning

confidence: 94%

“…Western blotting was performed as previously described 37 . In brief, ~2x10 6 cells were enzymatically lifted or gently scraped off cell culture dishes, and pelleted for 5 min at 600 x g. The supernatant was discarded, and the pellet resuspended in 100 µl of ice-cold RIPA lysis buffer containing 1x protease inhibitor cocktail (Roche), incubated for 30 min on ice, and centrifuged for 15 min at >15,000 x g to pellet cell debris and collect supernatant.…”

Section: Western Blottingmentioning

confidence: 99%

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Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Kargapolova

Rehimi

Kayserli³

et al. 2020

Preprint

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Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.

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DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

2019

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Here, the emerging data on DNA G‐quadruplexes (G4s) as epigenetic modulators are reviewed and integrated. This concept has appeared and evolved substantially in recent years. First, persistent G4s (e.g., those stabilized by exogenous ligands) were linked to the loss of the histone code. More recently, transient G4s (i.e., those formed upon replication or transcription and unfolded rapidly by helicases) were implicated in CpG island methylation maintenance and de novo CpG methylation control. The most recent data indicate that there are direct interactions between G4s and chromatin remodeling factors. Finally, multiple findings support the indirect participation of G4s in chromatin reshaping via interactions with remodeling‐related transcription factors (TFs) or damage responders. Here, the links between the above processes are analyzed; also, how further elucidation of these processes may stimulate the progress of epigenetic therapy is discussed, and the remaining open questions are highlighted.

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HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types

Cited by 185 publications

References 72 publications

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control

Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

DNA G‐Quadruplexes (G4s) Modulate Epigenetic (Re)Programming and Chromatin Remodeling

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