A5054214008- Ubiquitin and proteasome pathways
- Genetics and Neurodevelopmental Disorders
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Microtubule and mitosis dynamics
- Genomics and Rare Diseases
- 14-3-3 protein interactions
- MicroRNA in disease regulation
- RNA modifications and cancer
- Acute Myeloid Leukemia Research
- RNA Research and Splicing
- Genomic variations and chromosomal abnormalities
- Bone Tumor Diagnosis and Treatments
- Neuroendocrine regulation and behavior
- Receptor Mechanisms and Signaling
- Cancer Treatment and Pharmacology
- Hematopoietic Stem Cell Transplantation
- Infant Health and Development
- Neuroscience and Neuropharmacology Research
- Bone Metabolism and Diseases
- Histone Deacetylase Inhibitors Research
- Animal Vocal Communication and Behavior
- Congenital heart defects research
Walter and Eliza Hall Institute of Medical Research
2018-2025
The University of Melbourne
2023-2025
Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with inherent reversibility modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development treatments requires understanding protein function and models disease. Here, we provide mouse model Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) demonstrate...
In the conventional model of transcriptional activation, transcription factors bind to response elements and recruit co-factors, including histone acetyltransferases. Contrary this model, we show that acetyltransferase KAT7 (HBO1/MYST2) is required genome wide for H3 lysine 14 acetylation (H3K14ac). Examining neural stem cells, find H3K14ac are present not only at transcribed genes but also inactive genes, intergenic regions, in heterochromatin. were continued actively time loss...
The histone lysine acetyltransferase KAT6B (MYST4, MORF, QKF) is the target of recurrent chromosomal translocations causing hematological malignancies with poor prognosis. Using Kat6b germline deletion and overexpression in mice, we determined role hematopoietic system. We found that sustained fetal stem cell pool but did not affect viability or differentiation. was essential for normal levels H3 9 (H3K9) acetylation a previously proposed target, H3K23. Compound heterozygosity closely...
Heterozygous mutations in the histone lysine acetyltransferase gene KAT6B ( MYST4/MORF/QKF ) underlie neurodevelopmental disorders, but mechanistic roles of remain poorly understood. Here, we show that loss embryonic neural stem and progenitor cells (NSPCs) impaired cell proliferation, neuronal differentiation, neurite outgrowth. Mechanistically, resulted reduced acetylation at H3 9 expression key nervous system development genes NSPCs developing cortex, including SOX family, particular Sox2...
Loss of the gene encoding histone acetyltransferase KAT6B (MYST4/MORF/QKF) causes developmental brain abnormalities as well behavioral and cognitive defects in mice. In humans, heterozygous variants cause two disorders, Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS; OMIM:603736) genitopatellar (GTPTS; OMIM:606170). Although effects homozygous mutations have been documented humans mice, gain-of-function not reported. Here, we show that overexpression Kat6b mice caused aggression,...
Abstract Closely related genes typically display common essential functions but also functional diversification, ensuring retention of both throughout evolution. The histone lysine acetyltransferases KAT6A (MOZ) and KAT6B (QKF/MORF), sharing identical protein domain structure, are mutually exclusive catalytic subunits a multiprotein complex. Mutations in either or result congenital intellectual disability disorders human patients. In mice, loss function gene results distinct, severe...
ABSTRACT Inhibitor of growth 4 and 5 (ING4, ING5) are structurally similar chromatin-binding proteins in the KAT6A, KAT6B KAT7 histone acetyltransferase protein complexes. Heterozygous mutations KAT6A or gene cause human disorders with cardiac defects, but contribution their chromatin-adaptor to development is unknown. We found that Ing5−/− mice had isolated ventricular septal defects. Ing4−/−Ing5−/− embryos failed undergo chorioallantoic fusion arrested at embryonic day 8.5, displaying loss...
Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability and endocrine disorder caused by pathogenic variants of plant homeodomain finger gene 6 ( PHF6 ). An understanding the role in vivo development mammalian nervous system required to advance our knowledge how mutations cause BFLS. Here, we show that protein levels are greatly reduced cells derived from a subset patients with We report phenotypic, anatomical, cellular molecular characterization brain males females...
Abstract Trabid/ZRANB1 missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We characterised these patient cells and mice to identify key role for the regulation neurite growth. One flanked catalytic cysteine its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, failed bind STRIPAK, large multiprotein assembly...
ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We characterized these patient cells and mice to identify key role for the regulation neurite growth. One flanked catalytic cysteine its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, failed bind STRIPAK, large multiprotein assembly...
Trabid/ZRANB1 missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We characterised these patient cells and mice to identify key role for the regulation neurite growth. One flanked catalytic cysteine its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, failed bind STRIPAK, large multiprotein assembly implicated...
Trabid/ZRANB1 missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We characterised these patient cells and mice to identify key role for the regulation neurite growth. One flanked catalytic cysteine its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, failed bind STRIPAK, large multiprotein assembly implicated...
ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We characterized these patient cells and mice to identify key role for the regulation neurite growth. One flanked catalytic cysteine its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, failed bind STRIPAK, large multiprotein assembly...