Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses

Carmen Espejo-Serrano; Catriona Aitken; Beatrice F.  Tan; Danielle G. May; Rachel J.  Chrisopulos; Kyle J. Roux; Jeroen A. A.  Demmers; Samuel G.  Mackintosh; Joost  Gribnau; Francisco  Bustos; Cristina  Gontan; Greg M. Findlay

doi:10.26508/lsa.202302282

Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses

Carmen Espejo-Serrano, Catriona Aitken, Beatrice F. Tan, Danielle G. May, Rachel J. Chrisopulos, Kyle J. Roux, Jeroen A. A. Demmers, Samuel G. Mackintosh, Joost Gribnau, Francisco Bustos, Cristina Gontan, Greg M. Findlay (Lead / Corresponding author)

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Abstract

Protein ubiquitylation regulates key biological processes including transcription. This isexemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental geneexpression by ubiquitylating the REX1 transcription factor and is mutated in an X-linkedintellectual disability disorder. However, the precise mechanisms by which ubiquitylationdrives specific transcriptional responses are not known. Here, we show that RNF12 isrecruited to specific genomic locations via a consensus sequence motif, which enables colocalisationwith REX1 substrate at gene promoters. Surprisingly, RNF12 chromatinrecruitment is achieved via a non-catalytic basic region and comprises a previouslyunappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatintargeting is critical for REX1 ubiquitylation and downstream RNF12-dependent generegulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1axis and provide insight into mechanisms by which protein ubiquitylation enablesprogramming of gene expression.

Original language	English
Article number	e202302282
Number of pages	19
Journal	Life Science Alliance
Volume	7
Issue number	3
Early online date	10 Jan 2024
DOIs	https://doi.org/10.26508/lsa.202302282
Publication status	Published - Mar 2024

Keywords

E3 ubiquitin ligase
RNF12/RLIM
embryonic stem cells
protein ubiquitylation
genomic targeting
chromatin
developmental transcription.

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (miscellaneous)
Health, Toxicology and Mutagenesis
Plant Science
Ecology

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10.26508/lsa.202302282Licence: CC BY

Final Published VersionFinal published version, 3.39 MBLicence: CC BY

Functions and Applications of a Novel Pluripotency Signalling Pathway (Sir Henry Dale Fellowship)
Findlay, G. (Investigator)
1/09/18 → 31/08/23
Project: Research

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Espejo-Serrano, C., Aitken, C., Tan, B. F., May, D. G., Chrisopulos, R. J., Roux, K. J., Demmers, J. A. A., Mackintosh, S. G., Gribnau, J., Bustos, F., Gontan, C., & Findlay, G. M. (2024). Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses. Life Science Alliance, 7(3), Article e202302282. https://doi.org/10.26508/lsa.202302282

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title = "Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses",

abstract = "Protein ubiquitylation regulates key biological processes including transcription. This isexemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental geneexpression by ubiquitylating the REX1 transcription factor and is mutated in an X-linkedintellectual disability disorder. However, the precise mechanisms by which ubiquitylationdrives specific transcriptional responses are not known. Here, we show that RNF12 isrecruited to specific genomic locations via a consensus sequence motif, which enables colocalisationwith REX1 substrate at gene promoters. Surprisingly, RNF12 chromatinrecruitment is achieved via a non-catalytic basic region and comprises a previouslyunappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatintargeting is critical for REX1 ubiquitylation and downstream RNF12-dependent generegulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1axis and provide insight into mechanisms by which protein ubiquitylation enablesprogramming of gene expression.",

keywords = "E3 ubiquitin ligase, RNF12/RLIM, embryonic stem cells, protein ubiquitylation, genomic targeting, chromatin, developmental transcription.",

author = "Carmen Espejo-Serrano and Catriona Aitken and Tan, {Beatrice F.} and May, {Danielle G.} and Chrisopulos, {Rachel J.} and Roux, {Kyle J.} and Demmers, {Jeroen A. A.} and Mackintosh, {Samuel G.} and Joost Gribnau and Francisco Bustos and Cristina Gontan and Findlay, {Greg M.}",

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month = mar,

doi = "10.26508/lsa.202302282",

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AU - Espejo-Serrano, Carmen

AU - Aitken, Catriona

AU - Tan, Beatrice F.

AU - May, Danielle G.

AU - Chrisopulos, Rachel J.

AU - Roux, Kyle J.

AU - Demmers, Jeroen A. A.

AU - Mackintosh, Samuel G.

AU - Gribnau, Joost

AU - Bustos, Francisco

AU - Gontan, Cristina

AU - Findlay, Greg M.

PY - 2024/3

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N2 - Protein ubiquitylation regulates key biological processes including transcription. This isexemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental geneexpression by ubiquitylating the REX1 transcription factor and is mutated in an X-linkedintellectual disability disorder. However, the precise mechanisms by which ubiquitylationdrives specific transcriptional responses are not known. Here, we show that RNF12 isrecruited to specific genomic locations via a consensus sequence motif, which enables colocalisationwith REX1 substrate at gene promoters. Surprisingly, RNF12 chromatinrecruitment is achieved via a non-catalytic basic region and comprises a previouslyunappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatintargeting is critical for REX1 ubiquitylation and downstream RNF12-dependent generegulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1axis and provide insight into mechanisms by which protein ubiquitylation enablesprogramming of gene expression.

AB - Protein ubiquitylation regulates key biological processes including transcription. This isexemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental geneexpression by ubiquitylating the REX1 transcription factor and is mutated in an X-linkedintellectual disability disorder. However, the precise mechanisms by which ubiquitylationdrives specific transcriptional responses are not known. Here, we show that RNF12 isrecruited to specific genomic locations via a consensus sequence motif, which enables colocalisationwith REX1 substrate at gene promoters. Surprisingly, RNF12 chromatinrecruitment is achieved via a non-catalytic basic region and comprises a previouslyunappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatintargeting is critical for REX1 ubiquitylation and downstream RNF12-dependent generegulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1axis and provide insight into mechanisms by which protein ubiquitylation enablesprogramming of gene expression.

KW - E3 ubiquitin ligase

KW - RNF12/RLIM

KW - embryonic stem cells

KW - protein ubiquitylation

KW - genomic targeting

KW - chromatin

KW - developmental transcription.

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DO - 10.26508/lsa.202302282

M3 - Article

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SN - 2575-1077

VL - 7

JO - Life Science Alliance

JF - Life Science Alliance

IS - 3

M1 - e202302282

ER -

Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses

Abstract

Keywords

ASJC Scopus subject areas

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Projects

Functions and Applications of a Novel Pluripotency Signalling Pathway (Sir Henry Dale Fellowship)

Cite this