The Function And Molecular Mechanism Of Smarca4/Brg1 In Regulating Group 3 Innate Lymphoid Cells

Group 3 innate lymphoid cells(ILC3s),a subset of the innate lymphoid cells,are abundantly present in the intestine and are crucial regulators at the frontier of i m Mune-surveillance against infection.Compared to adaptive i m Mune cells,ILC3s play important role in early stages of infection by rapidly responding to infla m Matory stimuli.Such a trait is contributed by unique chromatin remodeling manner in ILC3s.But it is not clearly understood how chromatin remodelers orchestrate ILC3s and intestinal i m Munity.Brg1,encoded by gene Smarca4,act as a key regulator in SWI/SNF chromatin remodeling complex via its ATPase domain.In this project,we aim to explore the function and molecular mechanism of Smarca4/Brg1 in regulating ILC3s by deleting Smarca4 specifically in ILC3s using Rorc-cre.We found that Brg1 defecient ILC3s continuously accumulate in the lamina propria of intestine at adult age,which was caused by unrestricted proliferation proved by Ki-67 staining.Secondly,ILC3s highly expressed GM-CSF in the absence of Brg1,leading to spontaneous colitis in adult mice of the Rag1^-/-background.Thirdly,loss of Brg1 makes a great reduction of NKp46⁺ILC3s,accompanied by reduced expression of T-bet,a key regulator of NKp46⁺ILC3s differentiation.We further demonstrated that Brg1 associated SWI/SNF chromatin remodeler promoted the differentiation of NKp46^-ILC3s to NKp46⁺ILC3s by facilitating T-bet expression.Finally,we proved that Brg1 binds to the transcriptional regulatory region of T-bet encoding gene and facilitates its expression by enhancing chromatin accessibility.However,Brg1 restrains GM-CSF expression by binding to its locus and suppresses its transcription.In our project we discovered the main function and their molecular mechanism of Brg1associated SWI/SNF chromatin remodeler complex in regulating ILC3s:On the one hand,it provides a favorable chromatin condition for the early stage of NKp46⁺ILC3s differentiation;On the other hand,it restrains the proliferation and pro-infla m Matory function of ILC3s in response to infla m Matory stimuli.This is the first reported regulatory manner of Brg1 associated SWI/SNF chromatin remodeler complex in modulating ILC3s function and subset differentiation.Brg1 is a potential target for restraining the pro-infla m Matory function of ILC3s in epigenetic level,and also provides a theory for regulating ILC3s more specifically and efficiently.