Wellcome Trust [102349/Z/13/Z to A.H.T., 099677/Z/12/Z to H.W.K., 098024/Z/11/Z, 209400/Z/17/Z to R.J.K.]; Lister Institute of Preventive Medicine; European Research Council [681440]; Japan Agency for Medical Research and Development, AMEDCREST Programme. Funding for open access charge: Wellcome Trus

King, HW

Klose, RJ

Kondo, T

Koseki, H

Koseki, Y

Nakayama, M

Turberfield, AH

Nucleic Acids Research

English

CpG islands (CGIs) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression

Turberfield, Anne

King, Hamish

Klose, Robert

Oxford University Research Archive

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

Oxford University Research Archive (ORA)

Queen Mary Research Online

ORA - Oxford University Research Archive

ABSTRACT CpG islands (CGI) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression.Wellcome Trust [102349/Z/13/Z to A.H.T., 099677/Z/12/Z to H.W.K., 098024/Z/11/Z, 209400/Z/17/Z to R.J.K.]; Lister Institute of Preventive Medicine; European Research Council [681440]; Japan Agency for Medical Research and Development, AMED-CREST Programme. Funding for open access charge: Wellcome Trust

Turberfield, A

King, H

Klose, R

https://qmro.qmul.ac.uk/xmlui/bitstream/123456789/64455/2/King.%202019.%20KDM2%20proteins.pdf

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

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Oxford University Research Archive (ORA)

Queen Mary Research Online

ORA - Oxford University Research Archive

Queen Mary Research Online