The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

Mata-Garrido, Jorge; Chang-Marchand, Yunhua; Reisacher, Caroline; Ageron, Elisabeth; Guerrera, Ida Chiara; Casafont, Íñigo; Bruneau, Aurélia; Cherbuy, Claire; Dumay, Anne; Ogier–Denis, Éric; Batsché, Éric; Revêchon, Gwladys; Eriksson, Maria; Muchardt, Christian; Arbibe, Laurence

doi:10.1038/s41467-022-34556-3

Cited by 9 publications

(31 citation statements)

References 75 publications

(88 reference statements)

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“…In conclusion, our work identifies HP1γ as an epigenetic silencing pathway controlling IFN-γ response at the epithelial barrier. We suggest that the previously identified decline in HP1γ in IBD patients (Mata-Garrido et al, 2022)…”

Section: Discussionmentioning

confidence: 53%

“…We next sought to identify immune genes directly targeted by HP1. To that end, we crossed the RNA-seq data obtained from purified Cbx3 KO mice colon epithelium ((Mata-Garrido et al, 2022), GSE192800) with a publicly available HP1γ Chromatin immunoprecipitation-sequencing (ChIP-seq) performed in the HCT116, a colorectal cancer cell line ((Smallwood et al, 2012), GSE28115). This strategy led us to identify 68 genes as potential HP1γ target genes ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

“…We previously showed that the microbiota of Cbx3 KO mice was dysbiotic, with the overrepresentation of colitogenic bacterial species that may trigger the expression of interferon responsive genes in Cbx3 KO mice (Mata-Garrido et al, 2022). To circumvent this possibility, we generated colon organoids derived from WT or Cbx3 KO mice and stimulated them in vitro with IFN-γ ( Figure 3F ).…”

Section: Resultsmentioning

confidence: 99%

“…Colon crypt derived from 3 months aged male mice were isolated. Organoids were cultured in Matrigel as previously described (Mata-Garrido et al, 2022) After three days culture,…”

Section: Methodsmentioning

confidence: 99%

“…Yet, the regulatory mechanisms controlling the expression of STAT1 and its downstream target genes in the intestinal epithelium remains poorly understood. In an earlier study, we reported that the expression of the chromatin and alternative splicing regulator HP1γ was reduced in UC patients (Mata-Garrido et al, 2022). Importantly, HP1γ depletion in the mouse gut epithelium triggers IBD-like traits, including inflammation and dysbiosis.…”

Section: Introductionmentioning

confidence: 96%

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The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier

Chang

Mata-Garrido

Desterke

et al. 2022

Preprint

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Interferon gamma (IFN-γ) plays central roles in the pathophysiology of inflammatory bowel disease (IBD), both activating inflammatory responses and immunosuppressive functions. However, the epigenetic mechanisms controlling the expression of IFN-γ responsive genes at the gut epithelial barrier are not well understood. In this study, we identified the epigenetic regulator HP1γ as a transcriptional repressor of the IFN-γ-responsive genes STAT1 (signal transducer and activator of transcription 1) and PD-L1 (Programmed Cell Death Ligand 1). Accordingly, HP1γ gene inactivation in the mouse gut epithelium resulted in an immunopathology with a long-lasting up-regulation of STAT1 and PD-L1. Colon organoids models and in vitro cell lines showed that HP1γ deficiency primed STAT1 and PD-L1 expressions, ultimately sensitizing epithelial cells to IFN-γ stimulation. Chromatin immunoprecipitation experiments suggest that HP1 promoter tethering is involved in the silencing of gene expression. Overall, these results identify HP1γ as an epigenetic silencing pathway controlling the IFN-γ response at the epithelial barrier.

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Section: Discussionmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Colon crypt derived from 3 months aged male mice were isolated. Organoids were cultured in Matrigel as previously described (Mata-Garrido et al, 2022) After three days culture,…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 3 more Smart Citations

The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier

Chang

Mata-Garrido

Desterke

et al. 2022

Preprint

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Crosstalk between alternative splicing and inflammatory bowel disease: Basic mechanisms, biotechnological progresses and future perspectives

Zou,

Zan,

Jia

et al. 2023

Clinical & Translational Med

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BackgroundAlternative splicing (AS) is an omnipresent regulatory mechanism of gene expression that enables the generation of diverse splice isoforms from a single gene. Recently, AS events have gained considerable momentum in the pathogenesis of inflammatory bowel disease (IBD).MethodsOur review has summarized the complex process of RNA splicing, and firstly highlighted the potential involved molecules that target aberrant splicing events in IBD. The quantitative transcriptome analyses such as microarrays, next‐generation sequencing (NGS) for AS events in IBD have been also discussed.ResultsAvailable evidence suggests that some abnormal splicing RNAs can lead to multiple intestinal disorders during the onset of IBD as well as the progression to colitis‐associated cancer (CAC), including gut microbiota perturbations, intestinal barrier dysfunctions, innate/adaptive immune dysregulations, pro‐fibrosis activation and some other risk factors. Moreover, current data show that the advanced technologies, including microarrays and NGS, have been pioneeringly employed to screen the AS candidates and elucidate the potential regulatory mechanisms of IBD. Besides, other biotechnological progresses such as the applications of third‐generation sequencing (TGS), single‐cell RNA sequencing (scRNA‐seq) and spatial transcriptomics (ST), will be desired with great expectations.ConclusionsTo our knowledge, the current review is the first one to evaluate the potential regulatory mechanisms of AS events in IBD. The expanding list of aberrantly spliced genes in IBD along with the developed technologies provide us new clues to how IBD develops, and how these important AS events can be explored for future treatment.

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CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity

Xiang,

Mata-Garrido,

et al. 2024

EMBO Mol Med

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As an important immune stimulator and modulator, IFNγ is crucial for gut homeostasis and its dysregulation links to diverse colon pathologies, such as colitis and colorectal cancer (CRC). Here, we demonstrated that the epigenetic regulator, CBX3 (also known as HP1γ) antagonizes IFNγ signaling in the colon epithelium by transcriptionally repressing two critical IFNγ-responsive genes: STAT1 and CD274 (encoding Programmed death-ligand 1, PD-L1). Accordingly, CBX3 deletion resulted in chronic mouse colon inflammation, accompanied by upregulated STAT1 and CD274 expressions. Chromatin immunoprecipitation indicated that CBX3 tethers to STAT1 and CD274 promoters to inhibit their expression. Reversely, IFNγ significantly reduces CBX3 binding to these promoters and primes gene expression. This antagonist effect between CBX3 and IFNγ on STAT1/PD-L1 expression was also observed in CRC. Strikingly, CBX3 deletion heightened CRC cells sensitivity to IFNγ, which ultimately enhanced their chemosensitivity under IFNγ stimulation in vitro with CRC cells and in vivo with a syngeneic mouse tumor model. Overall, this work reveals that by negatively tuning IFNγ-stimulated immune genes’ transcription, CBX3 participates in modulating colon inflammatory response and CRC chemo-resistance.

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The Heterochromatin protein 1 is a regulator in RNA splicing precision deficient in ulcerative colitis

Cited by 9 publications

References 75 publications

The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier

The HP1γ epigenetic silencer dampens IFN-γ response at the gut epithelial barrier

Crosstalk between alternative splicing and inflammatory bowel disease: Basic mechanisms, biotechnological progresses and future perspectives

CBX3 antagonizes IFNγ/STAT1/PD-L1 axis to modulate colon inflammation and CRC chemosensitivity

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