Physical Interactions and Functional Coordination between the Core Subunits of Set1/Mll Complexes and the Reprogramming Factors

Abstract

Differentiated cells can be reprogrammed to the pluripotent state by overexpression of defined factors, and this process is profoundly influenced by epigenetic mechanisms including dynamic histone modifications. Changes in H3K4 methylation have been shown to be the predominant activating response in the early stage of cellular reprogramming. Mechanisms underlying such epigenetic priming, however, are not well understood. Here we show that the expression of the reprogramming factors (Yamanaka factors, Oct4, Sox2, Klf4 and Myc), especially Myc, directly promotes the expression of certain core subunits of the Set1/Mll family of H3K4 methyltransferase complexes. A dynamic recruitment of the Set1/Mll complexes largely, though not sufficiently in its own, explains the dynamics of the H3K4 methylation during cellular reprogramming. We then demonstrate that the core subunits of the Set1/Mll complexes physically interact with mainly Sox2 and Myc among the Yamanaka factors. We further show that Sox2 directly binds the Ash2l subunit in the Set1/Mll complexes and this binding is mediated by the HMG domain of Sox2. Functionally, we show that the Set1/Mll complex core subunits are required for efficient cellular reprogramming. We also show that Dpy30, one of the core subunits in the complexes, is required for the efficient target binding of the reprogramming factors. Interestingly, such requirement is not necessarily dependent on locus-specific H3K4 methylation. Our work provides a better understanding of how the reprogramming factors physically interact and functionally coordinate with a key group of epigenetic modulators to mediate transitions of the chromatin state involved in cellular reprogramming.

A positive feedback loop involving the Wnt/β-catenin/MYC/Sox2 axis defines a highly tumorigenic cell subpopulation in ALK-positive anaplastic large cell lymphoma

“…A recently published observation [21] that the target genes of MYC substantially overlap with those of Sox2 suggests that MYC or the MYC protein complex may physically direct Sox2 to the gene promoters, and facilitate its DNA binding. This concept is supported by a previously published data that MYC and Sox2 were found co-localized in a protein complex [22]. Furthermore, MYC has been recently reported to regulate gene expression as a general transcriptional amplifier [23, 24].…”

Hibernation impacts lysine methylation dynamics in the 13‐lined ground squirrel, Ictidomys tridecemlineatus

“…Enhanced amounts of liver ASH2L were found at the same time as RBBP5 levels were unchanged, opposite to the protein changes seen in skeletal muscle. Without complex members, ASH2L may bind pre‐existing H3K4 methyl‐modifications to recruit and promote the activities of histone acetyltransferases and demethylase enzymes that are specific to inhibitory methylation modifications (Yang, Augustin, Hu, & Jiang, ). Although speculative, epigenetic regulation of transcription by KMTs through noncatalytic activities has been shown to regulate the expression of numerous pathways during cellular growth or stress (Sarvan et al, ; Xu et al, ).…”

Low expression of ASH2L protein correlates with a favorable outcome in acute myeloid leukemia

“…ASH2L is mechanistically involved in regulating the transition between pluripotent and differentiated states by coordinating the activities of histone H3K4 methyltransferase complexes and transcription factors that drive the expression of pluripotency genes through its direct interactions with Sox2 and c-Myc. [9] Ash2L is widely expressed in the developing mouse embryo[10–12], with highest expression observed in the fetal lung and liver. [11] Mice lacking Ash2L die prior to implantation (E3.5–8.5), indicating that Ash2L is essential for viability.…”