Anti-MLL4 (internal region) polyclonal antibody

The pathophysiologic continuum of non-alcoholic fatty liver disease begins with steatosis. Despite recent advances in our understanding of the gene regulatory program directing steatosis, how it is orchestrated at the chromatin level is unclear. PPAR gamma 2 is a hepatic steatotic transcription factor induced by overnutrition. Here, we report that the histone H3 lysine 4 methyltransferase MLL4/KMT2D directs overnutrition-induced murine steatosis via its coactivator function for PPAR gamma 2. We demonstrate that overnutrition facilitates the recruitment of MLL4 to steatotic target genes of PPAR gamma 2 and their transactivation via H3 lysine 4 methylation because PPAR gamma 2 phosphorylated by overnutrition-activated ABL1 kinase shows enhanced interaction with MLL4. We further show that Ppar gamma 2 (encoding PPAR gamma 2) is also a hepatic target gene of ABL1-PPAR gamma 2-MLL4. Consistently, inhibition of ABL1 improves the fatty liver condition of mice with overnutrition by suppressing the pro-steatotic action of MLL4. Our results uncover a murine hepatic steatosis regulatory axis consisting of ABL1-PPAR gamma 2-MLL4, which may serve as a target of anti-steatosis drug development.

Mixed lineage leukemias (MLLs) are an evolutionarily conserved trithorax family of human genes that play critical roles in HOX gene regulation and embryonic development. MLL1 is well known to be rearranged in myeloid and lymphoid leukemias in children and adults. There are several MLL family proteins such as MLL1, MLL2, MLL3, MLL4, MLL5, Set1A and Set1B, and each possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity and has critical roles in gene activation and epigenetics. Although MLLs are recognized as major regulators of gene activation, their mechanism of action, target genes and the distinct functions of different MLLs remain elusive. Recent studies demonstrate that besides H3K4 methylation and HOX gene regulation, MLLs have much wider roles in gene activation and regulate diverse other genes. Interestingly, several MLLs interact with nuclear receptors and have critical roles in steroid-hormone-mediated gene activation and signaling. In this minireview, we summarize recent advances in understanding the roles of MLLs in gene regulation and hormone signaling and highlight their potential roles in mRNA processing.