Histone Variant H2A.X Plays Novel Roles in Cell Lineage Commitment and Genomic Stability in ESC and iPSC

Herein, we demonstrated that the cell lineage commitment is unexpectedly regulated by the novel functions of H2A.X, a histone variant which was only well-known for its role in genome integrity maintenance previously. Surprisingly, only in ESCs but not differentiated cells, H2A.X is specifically targeted to genomic regions encoding early embryonic and extra-embryonic lineage genes to repress their expression. In addition, H2A.X is also enriched at genomic regions sensitive to replication stress and maintains genomic stability thereat. Most interestingly, faithful H2A.X deposition plays critical roles in maintaining both cell lineage commitment and genome integrity in iPSC. In iPSC lines which support the development of "all-iPS" animals, H2A.X deposition faithfully recapitulates the ESC pattern and therefore, the genome stability and cell lineage commitment are maintained. In iPSC lines that fail to support embryonic development, defective H2A.X depositions result in aberrant upregulation of early embryonic and extra-embryonic lineage genes and H2A.X-dependent genome instability. Overall design: mRNA-Seq of WT ESC and H2A.X KO ESC; and 4N+, 4N- iPSC.

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Wu T, Liu Y, Wen D, Tseng Z, Tahmasian M, Zhong M, Rafii S, Stadtfeld M, Hochedlinger K, Xiao A