Principal Investigator Harvey Lodish
Chromatin modifications, such as histone modifications, are critical to maintain a stable pattern of either gene activation or repression in cell fate specification and terminal differentiation. Bill and Shilpa performed ChIP-seq on Ter119+ mouse fetal liver cells focusing on histone modifiers such as H3K4 di- and trimethylation, H3K4 dimethylation, H3K9 and H4K16 acetylation, H3K27 trimethylation and also RNA polymerase II. H3K4 tri- and dimethylation, H3K9 and H4K16 acetylation, along with RNA polymerase II binding, are generally associated with actively expressed transcripts such as Band3 and LMO2. However, some of the highly transcribed genes such as ferritin and Jag1 are only marked with H3K4 methylation, but not acetylated. Another interesting class of ‘trivalent’ genes is marked by H3K4 and H3K27 trimethylation and also H3K9 acetylation. Bill and Shilpa discovered that the active marks were present on both highly induced and highly repressed genes but increase significantly on induced genes before they are expressed, while repressive marks are present at relatively equal levels on repressed and induced genes. Even RNA Pol II was bound to promoters of repressed genes, but found to increase both at the promoter and along the gene body of induced genes, suggesting that proximal promoter pausing prevented elongation of repressed genes as Pol II was still present at their promoters. Only the level of the elongation mark, H3K79me2, was most correlated with the direction of expression of highly induced and highly repressed genes. Their recent publication reflects how histone modifications undergo dynamic changes during terminal erythroid differentiation even in rapidly condensing chromatin.