Skip to Main content Skip to Navigation
Journal articles

Citrullination of Histone H3 Interferes with HP1-Mediated Transcriptional Repression

Abstract : Multiple Sclerosis (MS) is an autoimmune disease associated with abnormal expression of a subset of cytokines, resulting in inappropriate T-lymphocyte activation and uncontrolled immune response. A key issue in the field is the need to understand why these cytokines are transcriptionally activated in the patients. Here, we have examined several transcription units subject to pathological reactivation in MS, including the TNFa and IL8 cytokine genes and also several Human Endogenous RetroViruses (HERVs). We find that both the immune genes and the HERVs require the heterochromatin protein HP1a for their transcriptional repression. We further show that the Peptidylarginine Deiminase 4 (PADI4), an enzyme with a suspected role in MS, weakens the binding of HP1a to tri-methylated histone H3 lysine 9 by citrullinating histone H3 arginine 8. The resulting de-repression of both cytokines and HERVs can be reversed with the PADI-inhibitor Cl-amidine. Finally, we show that in peripheral blood mononuclear cells (PBMCs) from MS patients, the promoters of TNFa, and several HERVs share a deficit in HP1a recruitment and an augmented accumulation of histone H3 with a double citrulline 8 trimethyl lysine 9 modifications. Thus, our study provides compelling evidence that HP1a and PADI4 are regulators of both immune genes and HERVs, and that multiple events of transcriptional reactivation in MS patients can be explained by the deficiency of a single mechanism of gene silencing.
Document type :
Journal articles
Complete list of metadata

https://hal-pasteur.archives-ouvertes.fr/pasteur-03525617
Contributor : Patrick ENGLAND Connect in order to contact the contributor
Submitted on : Friday, January 14, 2022 - 12:03:48 AM
Last modification on : Wednesday, June 1, 2022 - 9:36:08 AM
Long-term archiving on: : Friday, April 15, 2022 - 6:14:29 PM

File

H3 citrullination Sharma et al...
Publication funded by an institution

Licence


Distributed under a Creative Commons Attribution 4.0 International License

Identifiers

Collections

Citation

Priyanka Sharma, Saliha Azebi, Patrick England, Tove Christensen, Anné Møller-Larsen, et al.. Citrullination of Histone H3 Interferes with HP1-Mediated Transcriptional Repression. PLoS Genetics, Public Library of Science, 2012, 8 (9), pp.e1002934. ⟨10.1371/journal.pgen.1002934⟩. ⟨pasteur-03525617⟩

Share

Metrics

Record views

6

Files downloads

12