Transformation of Accessible Chromatin and 3D Nucleome Underlies Lineage Commitment of Early T Cells

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SummaryHow chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4+CD8+ T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment. The transcription factor BCL11B, a critical regulator of T cell commitment, is associated with increased chromatin interaction, and Bcl11b deletion compromised chromatin interaction at its target genes. We propose that these large-scale and concerted changes in chromatin organization present an energy barrier to prevent the cell from reversing its fate to earlier stages or redirecting to alternatives and thus lock the cell fate into the T lineages.Graphical AbstractHighlightsCommitment to T lineages is paired with global changes in the regulome and 3D nucleomeTransformation of these chromatin organizations is concerted for T cell commitmentConcerted changes of the regulome and 3D nucleome underlie transcriptomic changesBCL11B contributes to the maintenance of the 3D nucleome in T cellsCellular differentiation and cell-fate choice involve substantial chromatin reorganization. Through an integrative analysis of the regulome, 3D nucleome, and transcriptome, Hu and Cui et al. uncover abrupt global changes in the regulome and 3D nucleome at the DN2-to-DN3 transition, establishing a chromatin barrier to lock cell fate into the T lineages.

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