KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity

Turberfield, Anne H.; Kondo, Takashi; Nakayama, Manabu; Koseki, Haruhiko; King, Hamish W

doi:10.1101/561571

Cited by 10 publications

(20 citation statements)

References 97 publications

(15 reference statements)

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“…For Pol II and its phosphorylated forms, cChIP-seq was done as described previously (Turberfield et al 2019). Briefly, 5×10 7 ESCs (untreated and OHT-treated) were crosslinked in 10 ml 1x PBS with 1% formaldehyde (methanol-free, Thermo Scientific) for 10 min at 25°C and then quenched by addition of 125 mM glycine.…”

Section: Methodsmentioning

confidence: 99%

“…To assay chromatin accessibility, calibrated ATAC-seq was performed as described previously (Turberfield et al 2019). First, 1×10 7 ESCs (untreated and OHT-treated) were mixed with 4×10 6 Drosophila SG4 cells in 1x PBS and then lysed in 1 ml HS Lysis buffer (50 mM KCl, 10 mM MgSO 4 .7H 2 0, 5 mM HEPES, 0.05% NP40 (IGEPAL CA630), 1 mM PMSF, 3 mM DTT, 1xPIC (Roche)) for 1 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Nuclear and Histone Extracts For Immunoblottimentioning

confidence: 99%

Section: Calibrated Atac-seq (Catac-seq)mentioning

confidence: 99%

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BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Fursova

Turberfield

Blackledge

et al. 2020

Preprint

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Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications that are found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A mono-ubiquitylation (H2AK119ub1) which is enriched at Polycomb-repressed gene promoters, but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we discover that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 represses gene expression by counteracting transcription initiation from gene regulatory elements, causing reductions in transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes leading to their derepression, therefore explaining the original genetic characterisation of BAP1 as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification, without the need for elaborate gene-specific targeting mechanisms.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Preparation Of Nuclear and Histone Extracts For Immunoblottimentioning

confidence: 99%

Section: Calibrated Atac-seq (Catac-seq)mentioning

confidence: 99%

See 2 more Smart Citations

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Fursova

Turberfield

Blackledge

et al. 2020

Preprint

Self Cite

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“…2 CpG islands and H3K4me3. Heatmaps illustrating non-methylated DNA (BioCAP) [ 47 ], RNAPII (transcription) [ 267 ], H3K4me3, CFP1, SET1A [ 61 ] and MLL2 [ 25 ] ChIP-seq signal across all CpG islands in mouse embryonic stem cells. The heatmaps are ranked based on RNAPII signal.…”

Section: Cpg Islands and H3k4me3mentioning

confidence: 99%

Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation

Hughes

Kelley

Klose

2020

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The precise regulation of gene transcription is required to establish and maintain cell type-specific gene expression programs during multicellular development. In addition to transcription factors, chromatin, and its chemical modification, play a central role in regulating gene expression. In vertebrates, DNA is pervasively methylated at CG dinucleotides, a modification that is repressive to transcription. However, approximately 70% of vertebrate gene promoters are associated with DNA elements called CpG islands (CGIs) that are refractory to DNA methylation. CGIs integrate the activity of a range of chromatin-regulating factors that can post-translationally modify histones and modulate gene expression. This is exemplified by the trimethylation of histone H3 at lysine 4 (H3K4me3), which is enriched at CGI-associated gene promoters and correlates with transcriptional activity. Through studying H3K4me3 at CGIs it has become clear that CGIs shape the distribution of H3K4me3 and, in turn, H3K4me3 influences the chromatin landscape at CGIs. Here we will discuss our understanding of the emerging relationship between CGIs, H3K4me3, and gene expression.

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Histone lysine demethylases and their functions in cancer

Sterling

Menezes

Abbassi

et al. 2020

Intl Journal of Cancer

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Histone lysine demethylases (KDMs) are enzymes that remove the methylation marks on lysines in nucleosomes' histone tails. These changes in methylation marks regulate gene transcription during both development and malignant transformation. Depending on which lysine residue is targeted, the effect of a given KDM on gene transcription can be either activating or repressing, and KDMs can regulate the expression of both oncogenes and tumour suppressors. Thus, the functions of KDMs can be regarded as both oncogenic and tumour suppressive, contingent on cell context and the enzyme isoform. Finally, KDMs also demethylate nonhistone proteins and have a variety of demethylase‐independent functions. These epigenetic and other mechanisms that KDMs control make them important regulators of malignant tumours. Here, we present an overview of eight KDM subfamilies, their most‐studied lysine targets and selected recent data on their roles in cancer stem cells, tumour aggressiveness and drug tolerance.

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KDM2 proteins constrain transcription from CpG island gene promoters independently of their histone demethylase activity

Cited by 10 publications

References 97 publications

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

BAP1 constrains pervasive H2AK119ub1 to control the transcriptional potential of the genome

Understanding the interplay between CpG island-associated gene promoters and H3K4 methylation

Histone lysine demethylases and their functions in cancer

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