Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation

Abstract

Understanding the function of histone modifications across inducible genes in mammalian cells requires quantitative, comparative analysis of their fate during gene activation and identification of enzymes responsible. We produced high-resolution comparative maps of the distribution and dynamics of H3K4me3, H3K36me3, H3K79me2 and H3K9ac across c-fos and c-jun upon gene induction in murine fibroblasts. In unstimulated cells, continuous turnover of H3K9 acetylation occurs on all K4-trimethylated histone H3 tails; distribution of both modifications coincides across promoter and 5′ part of the coding region. In contrast, K36- and K79-methylated H3 tails, which are not dynamically acetylated, are restricted to the coding regions of these genes. Upon stimulation, transcription-dependent increases in H3K4 and H3K36 trimethylation are seen across coding regions, peaking at 5′ and 3′ ends, respectively. Addressing molecular mechanisms involved, we find that Huntingtin-interacting protein HYPB/Setd2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation, but not H3K36-mono- or dimethylation, in these cells. These studies reveal four distinct layers of histone modification across inducible mammalian genes and show that HYPB/Setd2 is responsible for H3K36 trimethylation throughout the mouse nucleus.

Chromatin maps, histone modifications and leukemia

“…Mammalian H3K36 methyltransferases include SMYD2, 46 NSD1 47 and the Set2 homolog HYPB/ SETD2. 48 H3K36 methyltransferase activity has also been suggested for ASH1. 49 NSD1 is of particular interest as it is involved in a leukemogenic translocation that depends on enzymatic activity of the methyltransferase domain.…”

Epigenetic inactivation of the Sotos overgrowth syndrome gene histone methyltransferase NSD1 in human neuroblastoma and glioma

“…S2), suggesting a more prominent role for NSD1 in establishing the trimethylated histone lysines residues. To reinforce the concept that NSD1 was the enzyme mainly responsible for the described histone trimethylated marks in our tumoral context, we analyzed the expression levels of other histone methyltransferases targeting these particular lysines, such as SET2 (HYPB/HIF-1, KMT3A) and SMYD2 (KMT3C), which specifically methylate H3-K36 (20,21), and Pr-SET7/8 (KMT5A) and SUV4-20h1,h2 (KMT5B,C), which have been implicated in the monomethylation and trimethylation of H4-K20 (22,23). We observed similar expression of these four enzymes in cancer cells with hypermethylated and unmethylated NSD1 (Fig.…”

Fine-tuning type I IFN signaling: A new chapter in the IFN saga

“…Among them, the authors identified mono-methylation on K525 residue (K525me1) of STAT1 to be critical for IFN-α-induced STAT1 interaction with JAK1 kinase and for phosphorylation, nuclear translocation, and DNA-binding activity of STAT1. Since SETD2 is a known histone methyltransferase that catalyzes the methylation of H3K36 [7,8], the authors further examined whether SETD2 is responsible for K525 methylation of STAT1. Indeed, SETD2-F2 overexpression enhanced the monomethylation of STAT1, whereas silencing of SETD2 reduced the K525me1 of STAT1 induced by IFN-α stimulation.…”