两篇Nat Immunol | 薛海晖团队揭示CD8+ T细胞耗竭的三维基因组调控机制
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TL;DR - Two companion Nature Immunology papers from Hai-Hui Xue's team (Hackensack Meridian) map how 3D chromatin architecture programs CD8+ T cell exhaustion, identifying CTCF-mediated enhancer activation/insulation and Id2/Id3-anchored chromatin hubs as fate determinants. It shifts exhaustion biology from linear transcriptional/epigenetic regulation to higher-order genome folding, offering structural targets for immunotherapy.
- Paper 1 (CUT&RUN, ATAC-seq, Hi-C): TEX-induced CTCF sites are enriched for AP1/Runx/T-bet motifs and mostly lack CTCF motifs (partner-TF recruited), while ~65% of invariant sites carry CTCF motifs but overlap open chromatin <30%, consistent with insulation.
- Conditional CTCF knockout severely impaired TEX expansion, reduced effector molecules and mitochondrial function, lost ~50% of TAD boundaries (aberrantly activating Ctla4, Tcf7), and caused promoter-proximal Pol II retention plus net chromatin closing at metabolic/effector loci.
- Paper 2 (Hi-C hub mapping): seven cell-state-specific self-associating interaction hubs track the transcriptome — the Id2 hub is TEX_EFF-specific; the Id3 hub persists from naive into TPEX but vanishes in TEX_EFF.
- Functionally, Id2 loss cut TEX_EFF by >80% (raising TPEX, upregulating stemness), Id3 loss reduced TPEX >8-fold; mechanistically Id2 complexes with E2A/Runx3/T-bet and Id3 with E2A/Runx3/Tcf1, with minimal overlap in their regulated ATAC sites.
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两篇Nat Immunol | 薛海晖团队揭示CD8+ T细胞耗竭的三维基因组调控机制
TL;DR - Two companion Nature Immunology papers from Hai-Hui Xue's team (Hackensack Meridian) map how 3D chromatin architecture programs CD8+ T cell exhaustion, identifying CTCF-mediated enhancer activation/insulation and Id2/Id3-anchored chromatin hubs as fate determinants. It shifts exhaustion biology from linear transcriptional/epigenetic regulation to higher-order genome folding, offering structural targets for immunotherapy.
- Paper 1 (CUT&RUN, ATAC-seq, Hi-C): TEX-induced CTCF sites are enriched for AP1/Runx/T-bet motifs and mostly lack CTCF motifs (partner-TF recruited), while ~65% of invariant sites carry CTCF motifs but overlap open chromatin <30%, consistent with insulation.
- Conditional CTCF knockout severely impaired TEX expansion, reduced effector molecules and mitochondrial function, lost ~50% of TAD boundaries (aberrantly activating Ctla4, Tcf7), and caused promoter-proximal Pol II retention plus net chromatin closing at metabolic/effector loci.
- Paper 2 (Hi-C hub mapping): seven cell-state-specific self-associating interaction hubs track the transcriptome — the Id2 hub is TEX_EFF-specific; the Id3 hub persists from naive into TPEX but vanishes in TEX_EFF.
- Functionally, Id2 loss cut TEX_EFF by >80% (raising TPEX, upregulating stemness), Id3 loss reduced TPEX >8-fold; mechanistically Id2 complexes with E2A/Runx3/T-bet and Id3 with E2A/Runx3/Tcf1, with minimal overlap in their regulated ATAC sites.