RT Journal Article
SR Electronic
T1 Lsd1 safeguards T-cell development via suppressing endogenous retroelements and interferon responses
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302042
DO 10.26508/lsa.202302042
VO 6
IS 10
A1 Xia, Miaoran
A1 Wang, Bingbing
A1 Sun, Wujianan
A1 Ji, Dengyu
A1 Zhou, Hang
A1 Huang, Xuefeng
A1 Yu, Minghang
A1 Su, Ziyang
A1 Chen, Ping
A1 Qu, Kun
A1 Wang, Xi
YR 2023
UL http://www.life-science-alliance.org/content/6/10/e202302042.abstract
AB The histone demethylase Lsd1 has been shown to play multiple essential roles in mammalian biology. However, its physiological functions in thymocyte development remain elusive. We observed that the specific deletion of Lsd1 in thymocytes caused significant thymic atrophy and reduced peripheral T cell populations with impaired proliferation capacity. Single-cell RNA sequencing combined with strand-specific total RNA-seq and ChIP-seq analysis revealed that ablation of Lsd1 led to the aberrant derepression of endogenous retroelements, which resulted in a viral mimicry state and activated the interferon pathway. Furthermore, the deletion of Lsd1 blocked the programmed sequential down-regulation of CD8 expression at the DP→CD4+CD8lo stage and induced an innate memory phenotype in both thymic and peripheral T cells. Single-cell TCR sequencing revealed the kinetics of TCR recombination in the mouse thymus. However, the preactivation state after Lsd1 deletion neither disturbed the timeline of TCR rearrangement nor reshaped the TCR repertoire of SP cells. Overall, our study provides new insight into the function of Lsd1 as an important maintainer of endogenous retroelement homeostasis in early T-cell development.