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bioRxiv · 10.1101/2025.07.16.664824

Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells

Lyu, P.·Agarwal, G.·Guo, C.-J.·Ye, T.·Weng, C.·Antoszewski, M.·Joubran, S.·Caulier, A.·Poeschla, M.·Sankaran, V. G.
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Abstract

The HOXA gene locus coordinates body patterning, hematopoiesis, and differentiation. While studying blood phenotype-associated variation within the HOXA locus, we identified a genetic variant, rs17437411, associated with globally reduced blood counts, protection from blood cancers, and variation in anthropometric phenotypes. We find that this variant disrupts the activity of a previously unstudied antisense long non-coding RNA (lncRNA) located between HOXA7 and HOXA9, which we have named HOTSCRAMBL. The HOTSCRAMBL variant disrupts lncRNA function and reduces human hematopoietic stem cell (HSC) self-renewal. Mechanistically, HOTSCRAMBL enables appropriate expression and splicing of HOXA genes in HSCs, most notably HOXA9, in an SRSF2-dependent manner. Given the critical role of HOXA gene expression in some blood cancers, we also demonstrate that HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias. Collectively, we show how insights from human genetic variation can uncover critical regulatory processes required for effective developmental gene expression.

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Lyu, P., Agarwal, G., Guo, C.-J., Ye, T., Weng, C., Antoszewski, M., Joubran, S., Caulier, A., Poeschla, M., Sankaran, V. G.. 2025-07-16. Genetic variation reveals a homeotic long noncoding RNA that modulates human hematopoietic stem cells. https://doi.org/10.1101/2025.07.16.664824

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