Abstract
KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.
Highlights
One striking theme emerging from recent findings from high throughput sequencing-based cancer genetic studies is that chromatin remodeling and histone modulators are frequently altered and that the resulting aberrations promote cancers
While the chromatin binding of the KMT2DΔSET mutant was detectable by chromatin immunoprecipitation (ChIP), we found that the removal of the SET domain of KMT2D led to a reduced level of H3K4me1 (Fig. S1C, Fig. 5B)
In an attempt to clarify the role of KMT2D in neoplastic cell proliferation, we characterized a panel of isogenic human cell lines, and provided evidence to support the notion that an inactivation of KMT2D may be detrimental to the ability of certain types of neoplastic cells to propagate
Summary
One striking theme emerging from recent findings from high throughput sequencing-based cancer genetic studies is that chromatin remodeling and histone modulators are frequently altered and that the resulting aberrations promote cancers. Germline KMT2D inactivation has recently been found to be the major cause of Kabuki syndrome [20], a rare, congenital pediatric disorder characterized by intellectual disabilities; de novo mutations in KMT2D and other chromatin-modifying genes have been associated with congenital heart disease [21]. These findings place the KMT2D/KMT2C pathway among the most frequently mutated pathogenic pathways that drive human diseases. We further characterized KMT2D binding loci to reveal a link between KMT2D, global H3K4 monomethylation, and enhancer elements
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