PMID:26691508

Citation	Yang, Z, Augustin, J, Hu, J and Jiang, H (2015) Physical Interactions and Functional Coordination between the Core Subunits of Set1/Mll Complexes and the Reprogramming Factors. PLoS ONE 10:e0145336
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.
Links	PubMed PMC4686221 Online version:10.1371/journal.pone.0145336
Keywords	Animals; Cells, Cultured; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Epigenesis, Genetic; Fibroblasts/cytology; Gene Knockdown Techniques; HEK293 Cells; Histone-Lysine N-Methyltransferase/genetics; Histone-Lysine N-Methyltransferase/metabolism; Humans; Methylation; Mice, Transgenic; Multiprotein Complexes/metabolism; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Octamer Transcription Factor-3/genetics; Octamer Transcription Factor-3/metabolism; Proteins/genetics; Proto-Oncogene Proteins c-myc/genetics; Proto-Oncogene Proteins c-myc/metabolism; SOXB1 Transcription Factors/genetics; SOXB1 Transcription Factors/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:PO5F1		GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific	ECO:0000314:		F		Protein Name: Oct 4 Uniprot ID: P20263 Notes: Fig. 1C and D shows that Mouse cells treated with Oct4 (a transcription factor identified in Uniprot as Pou5f1) exhibit increased mRNA levels of the genes Wdr5 and Dpy30 relative to the control. Fig 6B shows that Oct4 binds the promoter.	complete CACAO 13344
MOUSE:PO5F1		GO:0036207: positive regulation of histone gene expression	ECO:0000314:		P		Fig. 1C and D shows that Mouse cells treated with Oct4 exhibit increased mRNA levels of histone related genes Wdr5 and Actb relative to the control.	complete
MOUSE:PO5F1		GO:0060261: positive regulation of transcription initiation from RNA polymerase II promoter	ECO:0000314:		P		In Figure 1, more specifically 1C and 1D, it is shown how POU domain, class 5, transcription factor 1/Transcription Factor Oct4 in Mus musculus upregulates Wdr5 and Dpy30 expression at the RNA level. Figure 6B then shows occupation of the promoter sequence through ChIP assays for the POU domain, class 5, transcription factor 1/Transcription Factor Oct4.	complete CACAO 13461
MOUSE:CADH1		GO:1905437: positive regulation of histone H3-K4 trimethylation	ECO:0000314:		P		Fig. 2 (top panel) shows that in mice, levels of H3K4 trimethylation associated with the Cdh1 (identified in Uniprot as Cadherin-1 or CADH1) promoter increase during reprogramming.	complete CACAO 13394
MOUSE:KLF4		GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314:		P		Protein Name: Krueppel-like factor 4; Klf4 Organism: Mus musculus (Mouse) Notes: In Figure 1, more specifically 1C, it is shown how Krueppel-like factor 4/Klf4 in Mus musculus upregulates Wdr5 and Dpy30 expression at the RNA level	complete CACAO 13347
MOUSE:KLF4		GO:0036207: positive regulation of histone gene expression	ECO:0000314:		P		Fig. 1C and D shows that Mouse cells treated with Klf4 exhibit increased mRNA levels of histone related genes Wdr5 and Actb relative to the control.	complete CACAO 13355
MOUSE:MYC		GO:0036207: positive regulation of histone gene expression	ECO:0000314:		P		Fig. 1C and D shows that Mouse cells treated with c-Myc (Myc) exhibit increased mRNA levels of histone related genes Wdr5 and Actb relative to the control.	complete CACAO 13358
MOUSE:MYC		GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific	ECO:0000314:		F		In Figure 1, more specifically 1C, it is shown how Myc proto-oncogene protein/c-Myc in Mus musculus upregulates Wdr5 and Dpy30 expression at the RNA level. With Myc proto-oncogene protein/c-Myc significantly having an impact on how the other transcription factors acted, as shown by Figure 1E. Later in the paper, through the use of this data, it then verifies how direct binding to the promoter sequence caused DNA-binding transcription activator activity.	complete CACAO 13367
MOUSE:MYC		GO:0060261: positive regulation of transcription initiation from RNA polymerase II promoter	ECO:0000314:		P		In Figure 1, more specifically 1C and 1D, it is shown how Myc proto-oncogene protein/c-Myc in Mus musculus (Mouse) upregulates Wdr5 and Dpy30 expression at the RNA level. Fig 1H then shows that c-Myc binds to the promoter specifically.	complete CACAO 13418
MOUSE:SOX2		GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314:		P		Protein Name: Transcription factor SOX-2; Sox2 Organism: Mus musculus (Mouse) Notes: In Figure 1, more specifically 1C, it is shown how Transcription factor SOX-2/Sox2 in Mus musculus upregulates Wdr5 and Dpy30 expression at the RNA level	complete CACAO 13345
MOUSE:SOX2		GO:0036207: positive regulation of histone gene expression	ECO:0000314:		P		Fig. 1C and D shows that Mouse cells treated with Sox2 exhibit increased mRNA levels of histone related genes Wdr5 and Actb relative to the control.	complete CACAO 13354
MOUSE:IRF6		GO:1905437: positive regulation of histone H3-K4 trimethylation	ECO:0000314:		P		Fig. 2 (top panel) shows that in mice, levels of H3K4 trimethylation associated with the Irf6 promoter increase during reprogramming.	complete CACAO 13393
MOUSE:KMT2D		GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific	ECO:0000314:		F		Protein Name: c-Myc Uniprot ID: P01108 GO ID: G Notes: Fig. 1C and D shows that Mouse cells treated with c-Myc (a transcription factor identified in Uniprot as Myc) exhibit increased mRNA levels of the genes Wdr5 and Dpy30 relative to the control. Fig 1H shows that c-Myc binds the promoter.	complete CACAO 13349
MOUSE:FGF4		GO:1905437: positive regulation of histone H3-K4 trimethylation	ECO:0000314:		P		Fig. 2 (top panel) shows that in mice, levels of H3K4 trimethylation associated with the Fgf4 promoter increase during reprogramming.	complete CACAO 13363
MOUSE:SALL4		GO:1905437: positive regulation of histone H3-K4 trimethylation	ECO:0000314:		P		Fig. 2 (top panel) shows that in mice, levels of H3K4 trimethylation associated with the Sall4 promoter increase during reprogramming.	complete CACAO 13395

References

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