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

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• The HOXA gene locus is crucial for development, hematopoiesis, and differentiation.
• Genetic variations within the HOXA locus can influence blood cell counts and cancer susceptibility.

Purpose of the Study:

• To investigate a specific genetic variant (rs17437411) associated with blood phenotypes.
• To identify and characterize a novel antisense long non-coding RNA (lncRNA) involved in HOXA gene regulation.

Main Methods:

• Identification of the genetic variant rs17437411 and its association with blood counts and anthropometric phenotypes.
• Characterization of the HOTSCRAMBL lncRNA and its functional disruption by the variant.
• Analysis of HOTSCRAMBL's role in human hematopoietic stem cell (HSC) self-renewal and HOXA gene expression, including SRSF2 dependency.
• Evaluation of HOTSCRAMBL's impact on HOXA-dependent acute myeloid leukemias.

Main Results:

• The genetic variant rs17437411 disrupts the function of HOTSCRAMBL, a novel antisense lncRNA.
• HOTSCRAMBL disruption reduces human HSC self-renewal and impairs HOXA gene expression and splicing (e.g., HOXA9) in an SRSF2-dependent manner.
• HOTSCRAMBL variation or deletion compromises HOXA-dependent acute myeloid leukemias, highlighting its regulatory role in leukemogenesis.

Conclusions:

• Human genetic variation can uncover critical regulatory mechanisms in developmental gene expression.
• HOTSCRAMBL is a key regulator of HOXA gene expression in HSCs, influencing both normal hematopoiesis and leukemogenesis.
• Understanding HOTSCRAMBL function offers potential therapeutic targets for blood cancers.