Citrullination of Histone H3 Interferes with HP1-Mediated Transcriptional Repression

摘要: Multiple Sclerosis (MS) is an autoimmune disease associated with abnormal expression of a subset cytokines, resulting in inappropriate T-lymphocyte activation and uncontrolled immune response. A key issue the field need to understand why these cytokines are transcriptionally activated patients. Here, we have examined several transcription units subject pathological reactivation MS, including TNFα IL8 cytokine genes also Human Endogenous RetroViruses (HERVs). We find that both HERVs require heterochromatin protein HP1α for their transcriptional repression. further show Peptidylarginine Deiminase 4 (PADI4), enzyme suspected role weakens binding tri-methylated histone H3 lysine 9 by citrullinating arginine 8. The de-repression can be reversed PADI-inhibitor Cl-amidine. Finally, peripheral blood mononuclear cells (PBMCs) from MS patients, promoters TNFα, share deficit recruitment augmented accumulation double citrulline 8 tri-methyl modifications. Thus, our study provides compelling evidence PADI4 regulators HERVs, multiple events patients explained deficiency single mechanism gene silencing.