CXXC Finger Protein 1 Contains Redundant Functional Domains That Support Embryonic Stem Cell Cytosine Methylation, Histone Methylation, and Differentiation

Tate, Courtney M.; Lee, Jeong Heon; Skalnik, David G.

doi:10.1128/mcb.00243-09

Cited by 29 publications

(41 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous data indicated that retention of either the DNA-binding activity of Cfp1 or interaction with the Setd1 complexes is necessary for rescue of in vitro differentiation of CXXC1 -/-ES cells, suggesting that the CXXC and SID domains of Cfp1 are redundant functional domains [28]. Similarly, the data reported in this study reveals that ablation of the interaction between Cfp1 and methylated histone H3K4 does not affect the ability to rescue cellular differentiation of ES cells.…”

Section: Discussionsupporting

confidence: 65%

“…Similarly, the data reported in this study reveals that ablation of the interaction between Cfp1 and methylated histone H3K4 does not affect the ability to rescue cellular differentiation of ES cells. However, disruption of both the histone Previous data revealed that the C-terminal half of Cfp1 (361-656 aa) is sufficient for the rescue of in vitro differentiation in CXXC1 -/-ES cells [28]. However, the data reported here suggests that either the PHD domain or the CXXC domain is required to rescue defective ES cell differentiation in the context of full-length Cfp1.…”

Section: Discussionmentioning

confidence: 57%

“…However, a mutated form of Cfp1 containing both of these point mutations lacks rescue activity. Thus, while neither of these domains are required for rescue activity, retention of one of these domains is required, suggesting that these domains exhibit redundant activity in support of rescue activity [28]. To determine if a similar functional redundancy exists between the Cfp1 PHD and DNA-binding domains, the W49A and C169A mutations were introduced into full-length Cfp1.…”

Section: Interaction Of Cfp1 With Dna or Methylated Histone H3k4 Is Nmentioning

confidence: 99%

“…Using this approach, it was found that Cfp1 possesses redundant functional domains [28]. For example, the C169A mutation in the Cfp1 DNA-binding domain abolishes interaction with DNA [14], whereas the C375A mutation in the Cfp1 SID domain ablates interaction with the Setd1 complex [29].…”

Section: Introductionmentioning

confidence: 99%

“…However, introduction of both of these mutations into Cfp1 leads to a loss of rescue activity towards cellular differentiation. Therefore, the retention of either the DNA-binding activity or association with the Setd1 complexes is necessary for Cfp1 to support ES cell differentiation, suggesting that these domains have redundant function [28]. In contrast, rescue of appropriate sub-nuclear localization of H3K4me3 to euchromatin, as assessed by confocal microscopy, requires both the CXXC and the SID domains of Cfp1.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Efficient differentiation of murine embryonic stem cells requires the binding of CXXC finger protein 1 to DNA or methylated histone H3-Lys4

Mahadevan

Skalnik

2016

Gene

Self Cite

View full text Add to dashboard Cite

Mammalian CXXC finger protein 1 (Cfp1) is a DNA-binding protein that is a component of the Setd1 histone methyltransferase complexes and is a critical epigenetic regulator of both histone and cytosine methylation. Murine embryonic stem (ES) cells lacking Cfp1 exhibit a loss of histone H3-Lys4 tri-methylation (H3K4me3) at many CpG islands, and a mis-localization of this epigenetic mark to heterochromatic sub-nuclear domains.Furthermore, these cells fail to undergo cellular differentiation in vitro. These defects are rescued upon introduction of a Cfp1-expression vector. Cfp1 contains an N-terminal plant homeodomain (PHD), a motif frequently observed in chromatin associated proteins that functions as a reader module of histone marks. Here, we report that the Cfp1 PHD domain directly and specifically binds to histone H3K4me1/me2/me3 marks. Introduction of individual mutations at key Cfp1 PHD residues (Y28, D44, or W49) ablates this histone interaction both in vitro and in vivo. The W49A point mutation does not affect the ability of Cfp1 to rescue appropriate restriction of histone H3K4me3 to euchromatic subnuclear domains or in vitro cellular differentiation in Cfp1-null ES cells. Similarly, a mutated form of Cfp1 that lacks DNA-binding activity (C169A) rescues in vitro cellular differentiation. However, rescue of Cfp1-null ES cells with a double mutant form of Cfp1 (W49A, C169A) results in partially defective in vitro differentiation. These data define the Cfp1 PHD domain as a reader of histone H3K4me marks and provide evidence that this activity is involved in the regulation of lineage commitment in ES cells.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 57%

Section: Interaction Of Cfp1 With Dna or Methylated Histone H3k4 Is Nmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Efficient differentiation of murine embryonic stem cells requires the binding of CXXC finger protein 1 to DNA or methylated histone H3-Lys4

Mahadevan

Skalnik

2016

Gene

Self Cite

View full text Add to dashboard Cite

show abstract

Evolution of Eukaryotic Chromatin Proteins and Transcription Factors

et al. 2013

View full text Add to dashboard Cite

Differentially Expressed Epigenome Modifiers, Including Aurora Kinases A and B, in Immune Cells in Rheumatoid Arthritis in Humans and Mouse Models

Glant

Besenyei

Kádár

et al. 2013

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective The aim of this study was to identify epigenetic factors that are implicated in the pathogenesis of rheumatoid arthritis (RA) and to explore the therapeutic potential of the targeted inhibition of these factors. Methods PCR arrays were utilized to investigate the expression profile of genes that encod key epigenetic regulator enzymes. Mononuclear cells from RA patients and mice were monitored for gene expression changes, in association with arthritis development in murine models of RA. Selected genes were further characterized by quantitative real-time PCR, Western blot and flow cytometry methods. The targeted inhibition of the upregulated enzymes was studied in arthritic mice. Results A set of genes with arthritis-specific expression was identified by the PCR arrays. Aurora kinase A and B, both of which were highly expressed in arthritic mice and treatment naïve RA patients, were selected for detailed analysis. Elevated Aurora kinase expression was accompanied with an increased phosphorylation of histone H3, which promotes proliferation of T lymphocytes. Treatment with VX-680, a pan-Aurora kinase inhibitor, promoted B cell apoptosis, provided significant protection against the onset, and attenuated the inflammatory reactions in arthritic mice. Conclusions Arthritis development is accompanied the changes in the expression of a number of epigenome-modifying enzymes. Drug-induced downregulation of the Aurora kinases, among other targets, seems to be sufficient to treat experimental arthritis. Development of new therapeutics that target the Aurora kinases can potentially improve RA management.

show abstract

CXXC Finger Protein 1 Contains Redundant Functional Domains That Support Embryonic Stem Cell Cytosine Methylation, Histone Methylation, and Differentiation

Cited by 29 publications

References 65 publications

Efficient differentiation of murine embryonic stem cells requires the binding of CXXC finger protein 1 to DNA or methylated histone H3-Lys4

Efficient differentiation of murine embryonic stem cells requires the binding of CXXC finger protein 1 to DNA or methylated histone H3-Lys4

Evolution of Eukaryotic Chromatin Proteins and Transcription Factors

Differentially Expressed Epigenome Modifiers, Including Aurora Kinases A and B, in Immune Cells in Rheumatoid Arthritis in Humans and Mouse Models

Contact Info

Product

Resources

About