In the field of molecular biology, the Mi-2/NuRD (Nucleosome Remodeling Deacetylase) complex, is a group of associated proteins with both ATP-dependent chromatin remodeling and histone deacetylase activities. [1] [2] As of 2007 [update] , Mi-2/NuRD was the only known protein complex that couples chromatin remodeling ATPase and chromatin deacetylation enzymatic functions. [3]
In 1998, several independent groups reported the discovery of multi-enzyme complexes conferring both nucleosome remodelling and histone deacetylation activities. [4] [5] [6] [7] Xue et al [1] first described the human complex as the Nucleosome Remodelling and Deacetylase (NuRD) - this name has since been adopted for homologous complexes in most organisms.
The NuRD complex contains seven subunits: the histone deacetylase core proteins HDAC1 and HDAC2, the histone-binding proteins RbAp46 and RbAp48, the metastasis-associated proteins MTA1 (or MTA2 / MTA3), the methyl-CpG-binding domain protein MBD3 (or MBD2) and the chromodomain-helicase-DNA-binding protein CHD3 (aka Mi-2alpha) or CHD4 (aka Mi-2beta).
NuRD can be subdivided into two discrete subcomplexes which confer neuclosome remodelling or histone deacetylation activity,each of which retains catalytic activity without the presence of the other. [8] The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. [9] [10]
Mi-2/CHD4 may confer NuRD independent transcriptional regulation in some organisms and contexts. [11] For example, in the fly, Drosophila melanogaster, the majority of Mi2 biochemically purifies separately from the rest of the NuRD subunits [12] and profiling of NuRD component binding sites indicates that only a minority of loci are co-occupied by both Mi-2 and HDAC. [13] Similar results are reported in mouse embryonic stem cells where CHD4 shares only a minority of binding loci with core NuRD component, MBD3. [14] Independently of histone deacetylase, Mi-2 knockdown in neuronal tissue results in mis-expression of genes that are normally restricted to germline. [13] A similar observation was made in human erythroid cells, in which CHD4 but not Mi-2 is required for suppression of fetal globin genes. [15]
NuRD is traditionally thought of as a primarily repressive complex(in AP-1 [16] ), and in some contexts it is clear that it does confer this function. For example, NuRD is required to silence genes in neuronal differentiation. [17] However, more recent studies have presented a more nuanced picture of NuRD activity in which it is required for fine-tuning of gene expression during stem cell differentiation to ensure appropriate lineage specification. [14] [ dubious – discuss ]
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Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the HDAC1 gene.
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.
Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the HDAC2 gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the core histones. As such, it plays an important role in gene expression by facilitating the formation of transcription repressor complexes and for this reason is often considered an important target for cancer therapy.
Paired amphipathic helix protein Sin3a is a protein that in humans is encoded by the SIN3A gene.
Histone-binding protein RBBP4 is a protein that in humans is encoded by the RBBP4 gene.
Methyl-CpG-binding domain protein 2 is a protein that in humans is encoded by the MBD2 gene.
Metastasis-associated protein MTA1 is a protein that in humans is encoded by the MTA1 gene. MTA1 is the founding member of the MTA family of genes. MTA1 is primarily localized in the nucleus but also found to be distributed in the extra-nuclear compartments. MTA1 is a component of several chromatin remodeling complexes including the nucleosome remodeling and deacetylation complex (NuRD). MTA1 regulates gene expression by functioning as a coregulator to integrate DNA-interacting factors to gene activity. MTA1 participates in physiological functions in the normal and cancer cells. MTA1 is one of the most upregulated proteins in human cancer and associates with cancer progression, aggressive phenotypes, and poor prognosis of cancer patients.
Histone-binding protein RBBP7 is a protein that in humans is encoded by the RBBP7 gene.
Chromodomain-helicase-DNA-binding protein 3 is an enzyme that in humans is encoded by the CHD3 gene.
Methyl-CpG-binding domain protein 3 is a protein that in humans is encoded by the MBD3 gene.
Eukaryotic translation initiation factor 3 subunit A (eIF3a) is a protein that in humans is encoded by the EIF3A gene. It is one of the subunits of Eukaryotic initiation factor 3 (eIF3) a multiprotein complex playing major roles in translation initiation in eukaryotes.
Sin3A-associated protein, 30kDa, also known as SAP30, is a protein which in humans is encoded by the SAP30 gene.
Chromodomain-helicase-DNA-binding protein 4 is an enzyme that in humans is encoded by the CHD4 gene. CHD4 is the core nucleosome-remodelling component of the Nucleosome Remodelling and Deacetylase (NuRD) complex.
Metastasis-associated protein MTA2 is a protein that in humans is encoded by the MTA2 gene.
Memory is commonly referred to as the ability to encode, store, retain and subsequently recall information and past experiences in the human brain. This process involves many proteins, one of which is the Histone-binding protein RbAp48, encoded by the RBBP4 gene in humans.
H4K5ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H4 protein. H4K5 is the closest lysine residue to the N-terminal tail of histone H4. It is enriched at the transcription start site (TSS) and along gene bodies. Acetylation of histone H4K5 and H4K12ac is enriched at centromeres.
H3K23ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 23rd lysine residue of the histone H3 protein.
H3K56ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 56th lysine residue of the histone H3 protein.
Chromodomain helicase DNA-binding (CHD) proteins is a subfamily of ATP-dependent chromatin remodeling complexes (remodelers). All remodelers fall under the umbrella of RNA/DNA helicase superfamily 2. In yeast, CHD complexes are primarily responsible for nucleosome assembly and organization. These complexes play an additional role in multicellular eukaryotes, assisting in chromatin access and nucleosome editing.