Dataset Information

Mutations in BCOR, a co-repressor of CRX/OTX2, are associated with early-onset retinal degeneration.

ABSTRACT: Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduces their ability to activate the promoters of photoreceptor-specific genes. CUT&RUN sequencing further shows that BCOR shares genome-wide binding profiles with CRX/OTX2, consistent with a general co-repression activity. We also identify missense mutations in human BCOR in five families that have no evidence of cancer but present severe early-onset X-linked retinal degeneration. Last, we show that the human BCOR mutants cause degeneration when expressed in the mouse retina and have enhanced repressive activity on OTX2. These results uncover a role for BCOR in photoreceptors in both health and disease.

SUBMITTER: Langouet M

PROVIDER: S-EPMC9451151 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Mutations in <i>BCOR</i>, a co-repressor of <i>CRX/OTX2</i>, are associated with early-onset retinal degeneration.

Langouët Maéva M Jolicoeur Christine C Javed Awais A Mattar Pierre P Gearhart Micah D MD Daiger Stephen P SP Bertelsen Mette M Tranebjærg Lisbeth L Rendtorff Nanna D ND Grønskov Karen K Jespersgaard Catherine C Chen Rui R Sun Zixi Z Li Hui H Alirezaie Najmeh N Majewski Jacek J Bardwell Vivian J VJ Sui Ruifang R Koenekoop Robert K RK Cayouette Michel M

Science advances 20220907 36

Many transcription factors regulating the production, survival, and function of photoreceptor cells have been identified, but little is known about transcriptional co-regulators in retinal health and disease. Here, we show that BCL6 co-repressor (BCOR), a Polycomb repressive complex 1 factor mutated in various cancers, is involved in photoreceptor degenerative diseases. Using proteomics and transcription assays, we report that BCOR interacts with the transcription factors CRX and OTX2 and reduce ...[more]

PMID: 36070393

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Project description:Mutations in the Membrane-type frizzled related protein (Mfrp) gene results in an early-onset retinal degeneration associated with retinitis pigmentosa, microphthalmia, optic disc drusen and foveal schisis. In the current study, a previously characterized mouse model of human retinal degeneration carrying homozygous c.498_499insC mutations in Mfrp (MfrpKI/KI) was used. Patients carrying this mutation have retinal degeneration at an early age. The model demonstrates subretinal deposits and develops early-onset photoreceptor degeneration. We observed large subretinal deposits in MfrpKI/KI mice which were strongly CD68 positive and co-localized with autofluorescent spots. Single cell RNA sequencing of MfrpKI/KI mice retinal microglia showed a significantly higher number of pan-macrophage marker Iba-1 and F4/80 positive cells with increased expression of activation marker (CD68) and lowered microglial homeostatic markers (TMEM119, P2ry13, P2ry13, Siglech) compared with wild type mice confirming microglial activation as observed in retinal immunostaining showing microglia activation in subretinal region. Trajectory analysis identified a small cluster of microglial cells with activation transcriptomic signatures that could represent a subretinal microglia population in MfrpKI/KI mice expressing higher levels of APOE. We validated these findings using immunofluorescence staining of retinal cryosections and found a significantly higher number of subretinal Iba-1/ApoE positive microglia in MfrpKI/KI mice with some subretinal microglia also expressing lowered levels of microglial homeostatic marker TMEM119, confirming microglial origin. In summary, we confirm that MfrpKI/KI mice carrying the c.498_499insC mutation had a significantly higher population of activated microglia in their retina with distinct subsets of subretinal microglia. Further, studies are required to confirm whether the association of increased subretinal microglia in MfrpKI/KI mice are causal in degeneration.

Dataset Information

Mutations in BCOR, a co-repressor of CRX/OTX2, are associated with early-onset retinal degeneration.

Publications

Mutations in <i>BCOR</i>, a co-repressor of <i>CRX/OTX2</i>, are associated with early-onset retinal degeneration.

Similar Datasets

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