Peregrin also known as bromodomain and PHD finger-containing protein 1 is a protein that in humans is encoded by the BRPF1 gene located on 3p26-p25. Peregrin is a multivalent chromatin regulator that recognizes different epigenetic marks and activates three histone acetyltransferases ( Moz , Morf and Hbo1 ). BRPF1 contains two PHD fingers, one bromodomain and one chromo/Tudor-related Pro-Trp-Trp-Pro (PWWP) domain.
Brpf1 gene is very conserved and has a critical role in different developmental processes. [2] [3] [4] Zebrafish BRPF1, which is coordinated by its particular set of PWWP domains, mediates Moz -dependent histone acetylation and maintains Hox genes expression throughout vertebrate development, hence determines the proper pharyngeal segmental identities. [6] Furthermore, Brpf1 may not only has significant role for maintaining the anterior-posterior axis of the craniofacial skeleton, but also the dorsal-ventral axis of the caudal skeleton. [7] Recent studies have shown that ablation of the mouse Brpf1 gene causes embryonic lethality at embryonic day 9.5. [3] [4] Specifically, Brpf1 regulates placenta vascular formation, neural tube closure, primitive hematopoiesis and embryonic fibroblast proliferation. [3] [4]
For the central nervous system, Brpf1 has high expression and is essential for the development of several important structures, including neocortex and dentate gyrus in the hippocampus. [3] Brpf1 is dynamically expressed during forebrain development, especially the hippocampal neurogenesis. [5] Brpf1 shares phenotypes with transcription factors Sox2, Tlx and Tbr2 in dentate gyrus development and has potential link to neural stem cells and progenitors. [5] Except for the forebrain, Brpf1 is also required for the proper patterning of the craniofacial cartilage, which is derived from neural crest cells that migrate from the hindbrain. [8]
Recently, Brpf1 was reported to play the tumor suppressor or oncogenic role in several malignant tumors, including leukemia, medulloblastoma and endometrial stromal sarcoma. [2] [9] [10] [11] Brpf1 was considered a tumor suppressor gene because mutations in cancer cells appear to diminish the function of Brpf1 [9] [10] However, oncogenic role of Brpf1 is also possible in cancer. For example, Brpf1 can form a stable complex with Moz-Tif2, which could lead to the development of human acute myeloid leukemia (AML). [11] There is another Brpf1 related complex Brpf1–Ing5–Eaf6, which also plays a direct role in cancer. [2]
Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.
Histone deacetylases (EC 3.5.1.98, HDAC) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on both histone and non-histone proteins. HDACs allow histones to wrap the DNA more tightly. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. HDAC's action is opposite to that of histone acetyltransferase. HDAC proteins are now also called lysine deacetylases (KDAC), to describe their function rather than their target, which also includes non-histone proteins. In general, they suppress gene expression.
A bromodomain is an approximately 110 amino acid protein domain that recognizes acetylated lysine residues, such as those on the N-terminal tails of histones. Bromodomains, as the "readers" of lysine acetylation, are responsible in transducing the signal carried by acetylated lysine residues and translating it into various normal or abnormal phenotypes. Their affinity is higher for regions where multiple acetylation sites exist in proximity. This recognition is often a prerequisite for protein-histone association and chromatin remodeling. The domain itself adopts an all-α protein fold, a bundle of four alpha helices each separated by loop regions of variable lengths that form a hydrophobic pocket that recognizes the acetyl lysine.
The PHD finger was discovered in 1993 as a Cys4-His-Cys3 motif in the plant homeodomain proteins HAT3.1 in Arabidopsis and maize ZmHox1a. The PHD zinc finger motif resembles the metal binding RING domain (Cys3-His-Cys4) and FYVE domain. It occurs as a single finger, but often in clusters of two or three, and it also occurs together with other domains, such as the chromodomain and the bromodomain.
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.
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-lysine N-methyltransferase 2A, also known as acute lymphoblastic leukemia 1 (ALL-1), myeloid/lymphoid or mixed-lineage leukemia1 (MLL1), or zinc finger protein HRX (HRX), is an enzyme that in humans is encoded by the KMT2A gene.
Histone acetyltransferase KAT2A is an enzyme that in humans is encoded by the KAT2A gene.
Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene. It is also commonly identified as TIP60.
K(lysine) acetyltransferase 6A (KAT6A), is an enzyme that, in humans, is encoded by the KAT6A gene. This gene is located on human chromosome 8, band 8p11.21.
K(lysine) acetyltransferase 8 (KAT8) is an enzyme that in humans is encoded by the KAT8 gene.
K(lysine) acetyltransferase 6B (KAT6B) is an enzyme that in humans is encoded by the KAT6B gene.
JADE1 is a protein that in humans is encoded by the JADE1 gene.
ASH1L is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1.
Ming-Ming Zhou is an American scientist who focuses on structural and chemical biology, NMR spectroscopy, and drug design. He is the Dr. Harold and Golden Lamport Professor and Chairman of the Department of Pharmacological Sciences. He is also the co-director of the Drug Discovery Institute at the Icahn School of Medicine at Mount Sinai and Mount Sinai Health System in New York City, as well as Professor of Sciences. Zhou is an elected fellow of the American Association for the Advancement of Science.
Epigenetics of human development is the study of how epigenetics effects human development.
H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is a mark that indicates acetylation of the lysine residue at N-terminal position 27 of the histone H3 protein.
H2BK5ac is an epigenetic modification to the DNA packaging protein Histone H2B. It is a mark that indicates the acetylation at the 5th lysine residue of the histone H2B protein. H2BK5ac is involved in maintaining stem cells and colon cancer.
H4K16ac is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the acetylation at the 16th lysine residue of the histone H4 protein.
H4K91ac is an epigenetic modification to the DNA packaging protein histone H4. It is a mark that indicates the acetylation at the 91st lysine residue of the histone H4 protein. No known diseases are attributed to this mark but it might be implicated in melanoma.
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