HEXIM1 is an Essential Transcription Regulator During Human Erythropoiesis.

Regulation of RNA polymerase II (RNAPII) activity is an essential process that governs gene expression, however its contribution to the fundamental process of erythropoiesis remains unclear. HEXIM1 regulates RNAPII activity by controlling the location and activity of pTEFb (positive transcription factor beta). We identified a key role for HEXIM1 in controlling erythroid gene expression and function, with overexpression of HEXIM1 promoting erythroid proliferation and fetal globin expression. HEXIM1 regulated erythroid proliferation by enforcing RNAPII pausing at cell cycle check point genes and increasing RNAPII occupancy at genes that promote cycle progression. Genome-wide profiling of HEXIM1 revealed it was increased at both repressed and activated genes. Surprisingly, there were also genome-wide changes in the distribution of GATA1 and RNAPII. The most dramatic changes occurred at the beta globin loci, where there was loss of RNAPII and GATA1 at beta globin and gain of these factors at gamma globin. This resulted in increased expression of fetal globin, and BGLT3, a long non-coding RNA in the beta globin locus that regulates fetal globin expression. GATA1 was a key determinant of the ability of HEXIM1 to repress or activate gene expression. Genes that gained both HEXIM1 and GATA1 had increased RNAPII and increased gene expression, while genes that gained HEXIM1 but lost GATA1 had an increase in RNAPII pausing and decreased expression. Together, our findings reveal a central role for universal transcription machinery in regulating key aspects of erythropoiesis, including cell cycle progression and fetal gene expression, which could be exploited for therapeutic benefit.