The Chromatin Regulator Brpf1 Regulates Embryo Development and Cell Proliferation

You, Linya; Kou, Yan; Zou, Jinfeng; Zhang, Hong; Bertos, Nicholas; Park, Morag; Wang, Edwin; Yang, Xiang‐Jiao

doi:10.1074/jbc.m115.643189

Cited by 42 publications

(70 citation statements)

References 90 publications

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“…4 -7). Mouse BRPF1 is critical for embryogenesis (25,26) and forebrain development (26,28), whereas BRPF2 is required for erythropoiesis and thymocyte development (24,29). Our results about BRPF3 support that despite their high sequence homology (9), the three BRPF proteins have distinct functions in vivo (Fig.…”

Section: Discussionsupporting

confidence: 72%

“…All three acetyltransferases are authentic partners of BRPF1, but only HBO1 interacts with BRPF2 and BRPF3 as well. Mouse Brpf1 deficiency results in embryonic lethality at E9.5 (25,26) and Brpf2 deletion causes lethality at E15.5 (24). By contrast, Brpf3 is non-essential for mouse survival and development (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…9). This thus provides some explanation about why global and conditional Brpf1 knock-out mice display severe phenotypes, including embryonic lethality at E9.5 (25,26) and abnormal forebrain development (27,28). BRPF3 Is Non-essential for Mouse Development and Survival-About the biological function of BRPF3, mouse genetic analysis indicates that it is non-essential (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Although global loss of mouse Brpf1 led to embryonic lethality at E9.5, with severe defects in the vasculature and neural tube (25,26), forebrainspecific deletion caused abnormal cerebral and hippocampal development (27,28). Global inactivation of mouse Brpf2 resulted in embryonic lethality at E15.5, with growth retardation, abnormal eye development, and faulty erythropoiesis (24).…”

mentioning

confidence: 99%

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The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival

Kou

You

Degerny

et al. 2016

Journal of Biological Chemistry

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To interpret epigenetic information, chromatin readers utilize various protein domains for recognition of DNA and histone modifications. Some readers possess multidomains for modification recognition and are thus multivalent. Bromodomain-and plant homeodomain-linked finger-containing protein 3 (BRPF3) is such a chromatin reader, containing two plant homeodomain-linked fingers, one bromodomain and a PWWP domain. However, its molecular and biological functions remain to be investigated. Here, we report that endogenous BRPF3 preferentially forms a tetrameric complex with HBO1 (also known as KAT7) and two other subunits but not with related acetyltransferases such as MOZ, MORF, TIP60, and MOF (also known as KAT6A, KAT6B, KAT5, and KAT8, respectively). We have also characterized a mutant mouse strain with a lacZ reporter inserted at the Brpf3 locus. Systematic analysis of ␤-galactosidase activity revealed dynamic spatiotemporal expression of Brpf3 during mouse embryogenesis and high expression in the adult brain and testis. Brpf3 disruption, however, resulted in no obvious gross phenotypes. This is in stark contrast to Brpf1 and Brpf2, whose loss causes lethality at E9.5 and E15.5, respectively. In Brpf3-null mice and embryonic fibroblasts, RT-quantitative PCR uncovered no changes in levels of Brpf1 and Brpf2 transcripts, confirming no compensation from them. These results indicate that BRPF3 forms a functional tetrameric complex with HBO1 but is not required for mouse development and survival, thereby distinguishing BRPF3 from its paralogs, BRPF1 and BRPF2.In the past 2 decades or so, chromatin has been gradually recognized as an important signaling platform for regulation of diverse nuclear processes, thereby forming the foundation of epigenetic phenomena (1-4). Although chromatin modifiers confer or remove covalent modifications, chromatin readers recognize such modifications through different structural modules, including the methyl CpG-binding domain, bromodomain, chromodomain, plant homeodomain-linked (PHD) 4 finger and PWWP (Pro-Trp-Trp-Pro containing) domain (5-7). Such readers are crucial for transducing signals from various cellular and environmental cues to regulate the structure and function of chromatin in the nucleus. Some chromatin readers are multivalent because they contain multiple domains for recognition of different modifications. Human BRPF3 (bromodomain-and PHD finger-containing protein 3) is one such multivalent chromatin reader, comprising two PHD fingers joined by a C2HC zinc knuckle and followed by a bromodomain and a PWWP domain (8, 9). BRPF3 is paralogous to BRPF1 and BRPF2 (10, 11). These three human proteins form a subgroup within the bromodomain superfamily, within which there are 39 other members (12, 13).Several recent studies have provided insights into the molecular and biological functions of BRPF1 and BRPF2 (11,14). The bromodomain and PWWP domain of BRPF1 bind specifically to acetylated and methylated histone H3, respectively (15-18). Along with a connecting zinc knuckle, two PHD...

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival

Kou

You

Degerny

et al. 2016

Journal of Biological Chemistry

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“…Using the LacZ reporter, we determined the expression atlas and the results suggest an important role of mouse Brpf1 in different developmental processes [116]. Total knockout embryos die at E9.5, indicating an essential role in embryogenesis [116,117]. Because of high expression in the brain [116], we have recently generated forebrain-specific knockouts and discovered that Brpf1 is key to development of the cerebral cortex and hippocampus [63,118].…”

Section: Brpf1 and Its Paralogs In Animal Development And Human Diseasementioning

confidence: 97%

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

Yang

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Lysine residues are subject to many forms of covalent modification and one such modification is acetylation of the ε-amino group. Initially identified on histone proteins in the 1960s, lysine acetylation is now considered as an important form of post-translational modification that rivals phosphorylation. However, only about a dozen of human lysine acetyltransferases have been identified. Among them are MOZ (monocytic leukemia zinc finger protein; a.k.a. MYST3 and KAT6A) and its paralog MORF (a.k.a. MYST4 and KAT6B). Although there is a distantly related protein in Drosophila and sea urchin, these two enzymes are vertebrate-specific. They form tetrameric complexes with BRPF1 (bromodomain- and PHD finger-containing protein 1) and two small non-catalytic subunits. These two acetyltransferases and BRPF1 play key roles in various developmental processes; for example, they are important for development of hematopoietic and neural stem cells. The human KAT6A and KAT6B genes are recurrently mutated in leukemia, non-hematologic malignancies, and multiple developmental disorders displaying intellectual disability and various other abnormalities. In addition, the BRPF1 gene is mutated in childhood leukemia and adult medulloblastoma. Therefore, these two acetyltransferases and their partner BRPF1 are important in animal development and human disease.

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BRPF1‐associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development

Souza

Valle²,

Santos³

et al. 2022

American J of Med Genetics Pt A

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In 2017, Mattiolli et al. and Yan et al. described a series of patients with clinical findings essentially characterized by intellectual disabilities, ptosis, hypotonia, epilepsy, and weakness. They also found in these patients distinct heterozygous mutations in the BRPF1 gene, which plays a role in epigenetic regulation by promoting histone acetylation. The disease is known as Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP, OMIM #617333). Later, another 20 patients were also described by distinct reports, suggesting IDDDFP could be a more frequent cause of intellectual disability as it was thought before. Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination.The patient has a rare nonsense variant on exon 3 of BRPF1 gene. We also describe a phenotypic amplification for conditions related to deficiency in histone modifications.

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The Chromatin Regulator Brpf1 Regulates Embryo Development and Cell Proliferation

Cited by 42 publications

References 90 publications

The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival

The Chromatin Regulator BRPF3 Preferentially Activates the HBO1 Acetyltransferase but Is Dispensable for Mouse Development and Survival

MOZ and MORF acetyltransferases: Molecular interaction, animal development and human disease

BRPF1‐associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development

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