MLL histone methylases in estrogen‐mediated regulation of HOX genes involved in hair follicle development and leukemia

Abstract

Mixed lineage leukemias (MLLs) are human histone H3 lysine 4 specific methyl‐transferases that play critical roles in gene activation. MLLs are key players in HOX genes regulation. Although, MLL are well recognized as master players in HOX gene regulation and development, the mechanism of endocrine mediated HOX gene regulation and the roles of MLLs in this process is largely unknown. Our studies demonstrate that selected HOX genes such as HOXC13 are transcriptionally regulated by estrogen (E2). HOXC13 is a key player in hair follicle development and leukemia. HOXC13 promoter contains several estrogen response elements (EREs). Estrogen receptors (ERs) bind to these EREs (especially ERE1 and ERE2) in an E2‐depedent manner. Knockdown of ERa and ERb suppressed E2‐mediated activation of HOXC13. Similarly, knockdown of histone methylase MLL3 suppressed E2‐induced activation of HOXC13. Overall, our results demonstrated that MLL‐histone methylases in coordination with ERs, regulate HOXC13 gene expression in presence of steroid hormone estrogen implicating critical roles of HOXC13 as well as MLLs in hair follicle development and related diseases.This work is supported in parts by Texas Advanced Research program (ARP) and American Heart Association