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Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls gene-specific transcription

ABSTRACT: Protein ubiquitylation regulates key biological processes including transcription. This is exemplified by the E3 ubiquitin ligase RNF12/RLIM, which is mutated in an X-linked intellectual disability disorder and controls developmental gene expression by ubiquitylating the REX1 transcription factor. However, the precise mechanisms by which ubiquitylation patterns specific transcriptional programmes are not known. Here, we show that genomic targeting of RNF12 selectively programmes developmental transcription. RNF12 is recruited to specific genomic locations by recognising a distinct consensus sequence motif, which enables co-localisation with REX1. Surprisingly, RNF12 chromatin recruitment is achieved via the non-catalytic basic region (BR) and comprises a previously unappreciated autoinhibitory mechanism. Furthermore, RNF12 chromatin targeting is critical for REX1 ubiquitylation and downstream RNF12-dependent gene regulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1 axis and provides insight into mechanisms by which spatial control of protein ubiquitylation enables specific programming of gene expression.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Jeroen Demmers

LAB HEAD: Jeroen Demmers

PROVIDER: PXD047197 | Pride | 2024-01-09

REPOSITORIES: Pride

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			Action	DRS
	758_ChristinaGontan_01.RAW	Raw
	758_ChristinaGontan_02.RAW	Raw
	758_ChristinaGontan_03.RAW	Raw
	758_ChristinaGontan_04.RAW	Raw
	758_ChristinaGontan_05.RAW	Raw

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

Project description:Protein ubiquitylation regulates key biological processes including transcription. This is exemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental gene expression by ubiquitylating the REX1 transcription factor and is mutated in an X-linked intellectual disability disorder. However, the precise mechanisms by which ubiquitylation drives specific transcriptional responses are not known. Here, we show that RNF12 is recruited to specific genomic locations via a consensus sequence motif, which enables co-localisation with REX1 substrate at gene promoters. Surprisingly, RNF12 chromatin recruitment is achieved via a non-catalytic basic region and comprises a previously unappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatin targeting is critical for REX1 ubiquitylation and downstream RNF12-dependent gene regulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1 axis and provide insight into mechanisms by which protein ubiquitylation enables programming of gene expression.

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