Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation

Nadine Martin; Nikolay Popov; Francesca Aguilo; Ana O'Loghlen; Selina Raguz; Ambrosius P. Snijders; Gopuraja Dharmalingam; SiDe Li; Efstathia Thymiakou; Thomas Carroll; Bernd B. Zeisig; Chi Wai Eric So; Gordon Peters; Vasso Episkopou; Martin J. Walsh; Jesus Gil

doi:10.1038/emboj.2013.37

Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation

Nadine Martin, Nikolay Popov, Francesca Aguilo, Ana O'Loghlen, Selina Raguz, Ambrosius P. Snijders, Gopuraja Dharmalingam, SiDe Li, Efstathia Thymiakou, Thomas Carroll, Bernd B. Zeisig, Chi Wai Eric So, Gordon Peters, Vasso Episkopou, Martin J. Walsh, Jesus Gil^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

Abstract

The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.

Original language	English
Pages (from-to)	982-995
Number of pages	14
Journal	The EMBO journal
Volume	32
Issue number	7
DOIs	https://doi.org/10.1038/emboj.2013.37
Publication status	Published - 3 Apr 2013

Keywords

HLX1
Homeobox
Polycomb
p16(INK4a)
senescence
DEMETHYLASE JMJD3 CONTRIBUTES
CELLULAR SENESCENCE
GENE-EXPRESSION
INK4A-ARF LOCUS
STEM-CELLS
CANCER
IMMORTALIZATION
ACTIVATION
PATHWAYS
ROLES

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/emboj.2013.37

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Martin, N., Popov, N., Aguilo, F., O'Loghlen, A., Raguz, S., Snijders, A. P., Dharmalingam, G., Li, S., Thymiakou, E., Carroll, T., Zeisig, B. B., So, C. W. E., Peters, G., Episkopou, V., Walsh, M. J., & Gil, J. (2013). Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation. The EMBO journal, 32(7), 982-995. https://doi.org/10.1038/emboj.2013.37

@article{024f90784b8c4212a0baeecd7549453a,

title = "Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation",

abstract = "The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.",

keywords = "HLX1, Homeobox, Polycomb, p16(INK4a), senescence, DEMETHYLASE JMJD3 CONTRIBUTES, CELLULAR SENESCENCE, GENE-EXPRESSION, INK4A-ARF LOCUS, STEM-CELLS, CANCER, IMMORTALIZATION, ACTIVATION, PATHWAYS, ROLES",

author = "Nadine Martin and Nikolay Popov and Francesca Aguilo and Ana O'Loghlen and Selina Raguz and Snijders, {Ambrosius P.} and Gopuraja Dharmalingam and SiDe Li and Efstathia Thymiakou and Thomas Carroll and Zeisig, {Bernd B.} and So, {Chi Wai Eric} and Gordon Peters and Vasso Episkopou and Walsh, {Martin J.} and Jesus Gil",

year = "2013",

month = apr,

day = "3",

doi = "10.1038/emboj.2013.37",

language = "English",

volume = "32",

pages = "982--995",

journal = "The EMBO journal",

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Martin, N, Popov, N, Aguilo, F, O'Loghlen, A, Raguz, S, Snijders, AP, Dharmalingam, G, Li, S, Thymiakou, E, Carroll, T, Zeisig, BB , So, CWE, Peters, G, Episkopou, V, Walsh, MJ & Gil, J 2013, 'Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation', The EMBO journal, vol. 32, no. 7, pp. 982-995. https://doi.org/10.1038/emboj.2013.37

TY - JOUR

T1 - Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation

AU - Martin, Nadine

AU - Popov, Nikolay

AU - Aguilo, Francesca

AU - O'Loghlen, Ana

AU - Raguz, Selina

AU - Snijders, Ambrosius P.

AU - Dharmalingam, Gopuraja

AU - Li, SiDe

AU - Thymiakou, Efstathia

AU - Carroll, Thomas

AU - Zeisig, Bernd B.

AU - So, Chi Wai Eric

AU - Peters, Gordon

AU - Episkopou, Vasso

AU - Walsh, Martin J.

AU - Gil, Jesus

PY - 2013/4/3

Y1 - 2013/4/3

N2 - The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.

AB - The INK4/ARF locus regulates senescence and is frequently altered in cancer. In normal cells, the INK4/ARF locus is found silenced by Polycomb repressive complexes (PRCs). Which are the mechanisms responsible for the recruitment of PRCs to INK4/ARF and their other target genes remains unclear. In a genetic screen for transcription factors regulating senescence, we identified the homeodomain-containing protein HLX1 (H2.0-like homeobox 1). Expression of HLX1 extends cellular lifespan and blunts oncogene-induced senescence. Using quantitative proteomics, we identified p16(INK4a) as the key target mediating the effects of HLX1 in senescence. HLX1 represses p16(INK4a) transcription by recruiting PRCs and HDAC1. This mechanism has broader implications, as HLX1 also regulates a subset of PRC targets besides p16(INK4a). Finally, sampling members of the Homeobox family, we identified multiple genes with ability to repress p16(INK4a). Among them, we found HOXA9 (Homeobox A9), a putative oncogene in leukaemia, which also recruits PRCs and HDAC1 to regulate p16(INK4a). Our results reveal an unexpected and conserved interplay between homeodomain-containing proteins and PRCs with implications in senescence, development and cancer.

KW - HLX1

KW - Homeobox

KW - Polycomb

KW - p16(INK4a)

KW - senescence

KW - DEMETHYLASE JMJD3 CONTRIBUTES

KW - CELLULAR SENESCENCE

KW - GENE-EXPRESSION

KW - INK4A-ARF LOCUS

KW - STEM-CELLS

KW - CANCER

KW - IMMORTALIZATION

KW - ACTIVATION

KW - PATHWAYS

KW - ROLES

U2 - 10.1038/emboj.2013.37

DO - 10.1038/emboj.2013.37

M3 - Article

SN - 0261-4189

VL - 32

SP - 982

EP - 995

JO - The EMBO journal

JF - The EMBO journal

IS - 7

ER -

Interplay between Homeobox proteins and Polycomb repressive complexes in p16(INK4a) regulation

Abstract

Keywords

UN SDGs

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