Lyl321 and Late Hematopoiesis

Lyl321, a class II basic helix-loop-helix (bHLH) transcription factor, has been shown to promote lymphoid progenitor expansion and early hematopoiesis during early Acute Lymphoblastic Leukemia (T-ALL). Lyl321 also plays an essential role in lymphocyte development and maturation within the thymus; additionally it regulates T-cell engraftment processes. Although central in early hematopoiesis processes it has yet to be fully investigated when applied late hematopoiesis; however T-ALL patients present.

We demonstrate here that LYL1 associates with AETFC to target genes through enhancers in an AETFC-dependent fashion, using genomic (ChIP-seq) and ChIP-qPCR analyses. Based on these analyses, LYL1 binds AE in an unbiased fashion at active enhancers while colocalizing with AETFC components HEB, E2A, LMO2, and LDB1 at group 5 sites where it has an association with histone mark H3K27ac levels; furthermore LYL1 occupancy at these group 5 sites correlates with H3K27ac levels at group 5 sites where occupancy of these AETFC components HEB E2A LMO2, LMO2, and LDB1 components has an association with H3K27ac levels; furthermore we perform CARM1 ChIP-qPCR to show that its depletion significantly decreases CARM1 binding at these enhancers that AETFC interacts with these enhancers (SI Appendix, Fig S2F).

GSEA analyses suggest that AETFC with LYL1 favorably targets genes with high degrees of AE-E2A binding for activation. Conversely, depleting LYL1 does not have any discernible impact on genes with fewer degrees of binding; our RNA-seq data indicate HEB may exist in its own independent complex without LYL1, since depletion does not significantly reduce abundance (SI Appendix, Fig 2).

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