Regulation of muscle development by DPF3, a novel histone acetylation and methylation reader of the BAF chromatin remodeling complex

Abstract

Chromatin remodeling and histone modifications facilitate access of transcription factors to DNA by promoting the unwinding and destabilization of histone-DNA interactions. We present DPF3, a new epigenetic key factor for heart and muscle development characterized by a double PHD finger. DPF3 is associated with the BAF chromatin remodeling complex and binds methylated and acetylated lysine residues of histone 3 and 4. Thus, DPF3 may represent the first plant homeodomains that bind acetylated lysines, a feature previously only shown for the bromodomain. During development Dpf3 is expressed in the heart and somites of mouse, chicken, and zebrafish. Morpholino knockdown of dpf3 in zebrafish leads to incomplete cardiac looping and severely reduced ventricular contractility, with disassembled muscular fibers caused by transcriptional deregulation of structural and regulatory proteins. Promoter analysis identified Dpf3 as a novel downstream target of Mef2a. Taken together, DPF3 adds a further layer of complexity to the BAF complex by representing a tissue-specific anchor between histone acetylations as well as methylations and chromatin remodeling. Furthermore, this shows that plant homeodomain proteins play a yet unexplored role in recruiting chromatin remodeling complexes to acetylated histones.[Keywords: Heart and skeletal muscle development and function; PHD finger; BAF chromatin remodeling complex; SMARCD3-BAF60; acetylated and methylated histones; Mef2] Supplemental material is available at http://www.genesdev.org.

Double Plant Homeodomain (PHD) Finger Proteins DPF3a and -3b Are Required as Transcriptional Co-activators in SWI/SNF Complex-dependent Activation of NF-κB RelA/p50 Heterodimer

“…DPF2, which is ubiquitously expressed, is known to be involved in the processes of apoptosis in mouse myeloid cells following interleukin 3 (IL-3) deprivation (37). In normal cells, DPF3a/b was reported to be expressed specifically in cardiac and skeletal muscle and was critical for heart and muscle development (23). Because NF-B plays important roles in programmed cell death and development, these d4 proteins might be involved in these physiological phenomena through activating some specific NF-B dimers.…”

“…Importantly, transactivation mediated through RelA/p50 (Fig. 1C, lanes 14 -18 compared with lane 13), RelB/p52 (lanes 20 -24 compared with lane 19), and c-Rel/p50 (lanes 8 -12 compared with lane 7) was enhanced by the endogenous expression of any of the five candidate proteins (lanes [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. No significant differences were found among these five proteins in terms of the enhancement of any of the three NF-B dimers, suggesting that all potentially function as co-activators of NF-B in any context, at least when expressed at high levels.…”

“…The DPF3b protein shows all of the characteristics of a d4 family member, including binding activity to either methylated or acetylated lysine residues at histones H3 and H4 through the PHD fingers. However, DPF3a lacks these binding activities as it harbors a truncated d4 domain within its first PHD (23). Interestingly, two d4 family members, DPF1 (Neud4/BAF45b) and DPF3, and an additional protein, PHF10 (BAF45a), which also possesses double PHD fingers within its C terminus, have been reported to associate with the SWI/SNF complex in neural cells in a differentiation-specific manner (24).…”

Variants in DPF3 and DSCAML1 are associated with sperm morphology

“…DPF3 was previously implicated as a key epigenetic factor in development that facilitates access of transcription factors to DNA through interaction with histones, specifically by binding acetylated and methylated H3 and H4 lysine residues [12]. Results of recent studies emphasize the key role of histone modification, such as that regulated through DPF3, in preparing mature sperm DNA for early embryogenesis [13,14].…”

The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation

“…4 The YEATS domain has expanded the family of the acetyllysine readers, which currently comprises bromodomain, the double PHD finger (DPF) and the double pleckstrin homology (PH) domain. [6][7][8][9] While some acetyllysine readers are known to interact with acetyl marks broadly associated with active transcription, none had been shown to select for the H3K9ac mark commonly enriched at transcriptional start sites. 10,11 …”