Shaping the cellular landscape with Set2/SETD2 methylation

Abstract

Chromatin structure is a major barrier to gene transcription that must be disrupted and re-set during each round of transcription. Central to this process is the Set2/SETD2 methyltransferase that mediates co-transcriptional methylation to histone H3 at lysine 36 (H3K36me). Studies reveal that H3K36me not only prevents inappropriate transcriptional initiation from arising within gene bodies, but that it has other conserved functions that include the repair of damaged DNA and regulation of pre-mRNA splicing. Consistent with the importance of Set2/SETD2 in chromatin biology, mutations of SETD2, or mutations at or near H3K36 in H3.3, have recently been found to underlie cancer development. This review will summarize the latest insights into the functions of Set2/SETD2 in genome regulation and cancer development.

Histone methyltransferase SETD2 is required for meiotic maturation in mouse oocyte

“…As shown in Figure 7, compared with control oocytes, SETD2 depletion resulted in a drastic reduction of H3K36 tri-methylation in metaphase chromosomes, implying that H3K36me3 may be a potential target mediating the action of SETD2 on oocytes. SETD2, as a writer of methylational modification, regulates the maintenance of chromatin structure and genome stability, ensuring normal cell viability (McDaniel & Strahl, 2017;Pfister et al, 2014;Zhang, Cooper, & Brockdorff, 2015). In the current study, we showed that depletion of SETD2 in oocytes resulted in an abnormal spindle morphology and chromosome disorganization (Figure 3).…”

H3K36 Methylation Regulates Nutrient Stress Response in Saccharomyces cerevisiae by Enforcing Transcriptional Fidelity

“…In addition, TOR inhibitors combined with SETD2 knockdown is a lethal combination to leukemic cells (Zhu et al, 2014), suggesting that SETD2 and its role in enforcing transcriptional fidelity is likely conserved and important to the growth of cancer cells. As SETD2 is found mutated in a variety of cancers (McDaniel and Strahl, 2017), it will be of significant interest to determine the degree to which transcriptional fidelity regulated by SETD2/H3K36me3 contributes to its role in cancer development.…”

“…Set2 is a highly conserved histone methyltransferase that methylates histone H3 at lysine 36 (H3K36) (McDaniel and Strahl, 2017; Strahl et al, 2002; Venkatesh and Workman, 2015). In contrast to higher eukaryotes, Set2 is the sole H3K36 methyltransferase in Saccharomyces cerevisiae, and is responsible for modifying H3K36 with up to three methyl groups, creating mono-, di-, and tri-methylated H3K36.…”

“…In contrast to higher eukaryotes, Set2 is the sole H3K36 methyltransferase in Saccharomyces cerevisiae, and is responsible for modifying H3K36 with up to three methyl groups, creating mono-, di-, and tri-methylated H3K36. Significantly, evidence from yeast and human cells suggest that each H3K36 methyl state recruits distinct effector proteins (Carrozza et al, 2005; Gilbert et al, 2014; Keogh et al, 2005; McDaniel and Strahl, 2017; Smolle et al, 2012; Vermeulen et al, 2010), thereby increasing the signaling capacity of this highly conserved histone residue.…”

Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L‐dose dependency in HDAC1‐deficient thymic lymphoma

“…HDAC1 and HDAC2, prominent members of the class I HDACs, are found in the repressive Sin3, NuRD, and CoREST complexes (Yang & Seto, 2008). Loss or inhibition of HDAC1/Rpd3 leads to increased histone acetylation, which in turn can lead to increased expression of target genes and cryptic transcripts (Carrozza et al, 2005;Joshi & Struhl, 2005;Li et al, 2007;Rando & Winston, 2012;Brocks et al, 2017;McDaniel & Strahl, 2017).…”