PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex

Link, Stephanie; Spitzer, Ramona M. M.; Sana, Maryam; Torrado, Mario; Völker-Albert, Moritz; Keilhauer, Eva C.; Burgold, Thomas; Pünzeler, Sebastian; Low, Jason K. K.; Lindström, Ida; Nist, Andrea; Regnard, Catherine; Stiewe, Thorsten; Hendrich, Brian; Imhof, Axel; Mann, Matthias; Mackay, Joel P.; Bartkuhn, Marek; Hake, Sandra B.

doi:10.1038/s41467-018-06665-5

Cited by 49 publications

(74 citation statements)

References 66 publications

(105 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The majority of interactions with non-NuRD components was lost after Mbd3 deletion, indicating that most of these proteins do not directly associate either with the MTA proteins or with the deacetylase subcomplex ( Fig 1C). Exceptions to this were Zfp296, which was identified as interacting with all three MTA proteins in an Mbd3-independent manner, and Pwwp2a, which copurified with Mta1 in both wild-type and Mbd3-null cells, consistent with recent reports (Link et al, 2018;Zhang et al, 2018). Notably, Zfp219 and Zfp512b both showed Mbd3-independent interactions specifically with Mta2 ( Fig 1C).…”

Section: Mta Proteins Are Not Mutually Exclusive Within the Nurd Compsupporting

confidence: 90%

“…Functional and genetic data indicate that the CHD4‐containing remodelling subunit is capable of functioning independently of intact NuRD (O'Shaughnessy & Hendrich, ; O'Shaughnessy‐Kirwan et al , ; Ostapcuk et al , ). The deacetylase subcomplex has been shown biochemically to exist outside of intact NuRD, though whether this subcomplex has any specific function is not clear (Link et al , ; Zhang et al , ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

et al. 2019

Self Cite

View full text Add to dashboard Cite

Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often found as multiple paralogous proteins in vertebrate complexes. In some cases, these paralogues specify distinct biochemical and/or functional activities in vertebrate cells. Here, we set out to define the biochemical and functional diversity encoded by one such group of proteins within the mammalian Nucleosome Remodelling and Deacetylation (Nu RD ) complex: Mta1, Mta2 and Mta3. We find that, in contrast to what has been described in somatic cells, MTA proteins are not mutually exclusive within embryonic stem (ES) cell Nu RD and, despite subtle differences in chromatin binding and biochemical interactions, serve largely redundant functions. ES cells lacking all three MTA proteins exhibit complete Nu RD loss of function and are viable, allowing us to identify a previously unreported function for Nu RD in reducing transcriptional noise, which is essential for maintaining a proper differentiation trajectory during early stages of lineage commitment.

show abstract

Section: Mta Proteins Are Not Mutually Exclusive Within the Nurd Compsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…The acquisition of additional copies of a gene through duplication events provides opportunities for the development of unique gene products with distinct regulatory mechanisms (2). Functional divergence can result from gene duplications and protein paralog identity can influence the composition of large protein complexes (3). However, the consequences of paralog switching are largely overlooked during the characterization of proteins, protein complexes, and protein interaction networks.…”

Section: Discussionmentioning

confidence: 99%

Differential complex formation via paralogs in the human Sin3 protein interaction network

Adams

Banks

Thornton

et al. 2019

Preprint

View full text Add to dashboard Cite

Despite the continued analysis of HDAC inhibitor efficacy in clinical trials, the heterogeneous nature of the protein complexes they target limits our understanding of the beneficial and off-target effects associated with their application. Among the many HDAC protein complexes found within the cell, Sin3 complexes are conserved from yeast to humans and likely play important roles as regulators of transcriptional activity. The functional attributes of these protein complexes remain poorly characterized in humans. Contributing to the poor definition of Sin3 complex attributes in higher eukaryotes is the presence of two Sin3 scaffolding proteins, SIN3A and SIN3B. Here we show that paralog switching influences the interaction networks of the Sin3 complexes. While SIN3A and SIN3B do have unique interaction network components, we find that SIN3A and SIN3B interact with a common set of proteins.Additionally, our results suggest that SIN3A and SIN3B may possess the capacity to form hetero-oligomeric complexes. While one principal form of SIN3B exists in humans, the analysis of rare SIN3B proteoforms provides insight into the domain organization of SIN3B. Together, these findings shed light on the shared and divergent properties of human Sin3 proteins and highlight the heterogeneous nature of the complexes they organize.

show abstract

“…Recently, we demonstrated that the chromatin-binding protein PWWP2A, which can selectively recognize H2A.Z-containing nucleosomes (42,43), interacts robustly with the MTA, HDAC and RBBP subunits of NuRD. Surprisingly, however, GATAD2, MBD and CHD are not detected as interaction partners in these affinity-purification based experiments, suggesting that the two enzymatic activities in NuRD might in some situations be separable.…”

Section: Ino80mentioning

confidence: 99%

“…The subunit stoichiometry is also uncertain; recent studies using label-free mass spectrometry (33)(34)(35)(36)(37)(38) have yielded variable results that are often at odds with the stoichiometries demonstrated in the known subcomplex structures.The mechanisms by which NuRD selects target sites are also poorly understood. Transcriptional regulators such as FOG1 (22,39) and BCL11A (40,41) can bind to NuRD via the RBBP subunits but this mechanism is likely to account for only a small proportion of NuRD-genome interactions.Recently, we demonstrated that the chromatin-binding protein PWWP2A, which can selectively recognize H2A.Z-containing nucleosomes (42,43), interacts robustly with the MTA, HDAC and RBBP subunits of NuRD. Surprisingly, however, GATAD2, MBD and CHD are not detected as interaction partners in these affinity-purification based experiments, suggesting that the two enzymatic activities in NuRD might in some situations be separable.Against this background, we have used structural, biophysical and biochemical data to define the architecture of the NuRD complex.…”

mentioning

confidence: 99%

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

Low

Silva

Tabar

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The Nucleosome Remodeling and Deacetylase (NuRD) complex is essential for development in complex animals but has been refractory to biochemical analysis. We present the first integrated analysis of the architecture of the native mammalian NuRD complex, combining quantitative mass spectrometry, covalent cross-linking, protein biochemistry and electron microscopy. NuRD is built around a 2:2:4 pseudo-symmetric deacetylase module comprising MTA, HDAC and RBBP subunits. This module interacts asymmetrically with a remodeling module comprising one copy each of MBD, GATAD2 and CHD subunits. The previously enigmatic GATAD2 controls the asymmetry of the complex and directly recruits the ATP-dependent CHD remodeler. Unexpectedly, the MTA-MBD interaction acts as a point of functional switching. The transcriptional regulator PWWP2A modulates NuRD assembly by competing directly with MBD for binding to the MTA-HDAC-RBBP subcomplex, forming a 'moonlighting' PWWP2A-MTA-HDAC-RBBP complex that likely directs deacetylase activity to PWWP2A target sites. Taken together, our data describe the overall architecture of the intact NuRD complex and reveal aspects of its structural dynamics and functional plasticity. INO80(1, 2) and SWR1 complexes (3), as well as to the Snf2 (4) and Chromodomain-Helicase-DNA-binding 1 (CHD1) remodelers (5), our understanding of how such enzymes bring about remodeling is still underdeveloped. This is particularly true for the nucleosome remodeling and deacetylase (NuRD) complex.The NuRD complex is widely distributed among Metazoans and is expressed in most, if not all, tissues. It is essential for normal development (6, 7) and is a key regulator in the reprogramming of differentiated cells into pluripotent stem cells (8-10). Age-related reductions in NuRD subunit levels are strongly associated with memory loss, metastatic potential in human cancers (11), and the accumulation of chromatin defects (12, 13).The mammalian NuRD complex comprises at least six subunits (Figure S1a), and for each subunit there are at least two paralogues, giving the potential for significant compositional heterogeneity. CHD4 (and its paralogues CHD3 and -5) is the ATP-dependent DNA translocase in the complex and harbours several regulatory and targeting domains. For example, the PHD domains of CHD4 can recognize histone H3 N-terminal tails bearing methyllysine marks (14-16), and the HMG domain has been shown to bind to poly-ADP(ribose) (17). What distinguishes NuRD from many other remodelers is that it harbours a second catalytic activity, imparted by the histone deacetylases HDAC1 and -2. MBD2 and -3 can bind hydroxymethylated and/or methylated , and RBBP4 and -7 can each bind histone tails (21) and other transcriptional regulators (22,23). The metastasis-associated proteins MTA1, -2 and -3 contain several domains that are associated with nucleosome recognition, whereas GATAD2A and GATAD2B bind to both 25) and CHD proteins (25, 26) but otherwise do not have known functions. Some structural information is available for portions of t...

show abstract

PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex

Cited by 49 publications

References 66 publications

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

Differential complex formation via paralogs in the human Sin3 protein interaction network

The Nucleosome Remodeling and Deacetylase complex has an asymmetric, dynamic, and modular architecture

Contact Info

Product

Resources

About