The many lives of KATs — detectors, integrators and modulators of the cellular environment

Sheikh, Bilal N.; Akhtar, Asifa

doi:10.1038/s41576-018-0072-4

Cited by 140 publications

(149 citation statements)

References 296 publications

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“…This indicates that other KATs must maintain acetylation levels at these loci. Consistent with this hypothesis, our RNA-seq screen shows that other KATs such as Gcn5/KAT2A, Tip60/KAT5 and MOF/KAT8, which are expressed in neurons and localize to promoters 50, 51 , are not downregulated in dKAT3-ifKO neurons ( Fig. S11e, right shows the profile of Kat5 , a similar pattern is observed in Kat2A and Kat8 ).…”

Section: Discussionsupporting

confidence: 77%

Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

Lipiński

Muñoz‐Viana

Blanco

et al. 2019

Preprint

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27 Very little is known about the mechanisms responsible for maintaining cell 28 identity in mature tissues. The paralogous type 3 lysine acetyltransferases 29 (KAT3) CBP and p300 are both essential during development, but their 30 specific functions in nondividing differentiated cells remains unclear. Here, we 31 show that when both proteins are simultaneously knocked-out in excitatory 32 neurons of the adult brain, the mice express a rapidly progressing 33 neurological phenotype associated with reduced dendritic complexity and 34 electrical activity, the transcriptional shutdown of neuronal genes, and a 35 dramatic loss of H3K27 acetylation and pro-neural transcription factor binding 36 at neuronal enhancers. The neurons lacking both KAT3 rapidly acquire a 37 molecularly undefined fate with no sign of dedifferentiation, transdifferentiation 38 or death. Restoring CBP expression or lysine acetylation reestablished 39 neuronal-specific transcription. Our experiments demonstrate that KAT3 40 proteins act as fate-keepers in excitatory neurons and other cell types by 41 jointly safeguarding chromatin acetylation levels at cell type-specific 42 enhancers throughout life. 43 44 150 words 45 46 3 Lipinski et al.

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Section: Discussionsupporting

confidence: 77%

Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

Lipiński

Muñoz‐Viana

Blanco

et al. 2019

Preprint

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“…5a-e). In order to assess whether other lysine acetyltransferases (KATs) could regulate PINK1-dependent mitophagy, the pUb(Ser65) screen was repeated in POE SHSY5Y cells silenced for 22 other KATs 23,24 . Only KAT8 KD led to a decreased pUb(Ser65) signal, emphasising the specificity of the KAT8 KD effect on pUb(Ser65) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele

Melandri

O’Callaghan

et al. 2020

Preprint

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Parkinson’s disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding of the PD genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial PD, but its relevance to idiopathic PD is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through GWAS. We identified two new regulators of PINK1-mitophagy, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings establish PINK1-mitophagy as a contributing factor to idiopathic PD. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. Our data provide evidence that this assignment is likely to be incorrect and that variability at KANSL1 underpins this association. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

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“…HATs are classified based on structural and sequence homology into distinct groups including the p300/CBP, MYST and GCN5 families 14 . They play a central role in transcriptional regulation through their function to catalyze the transfer of acetyl groups from acetyl-CoA to the ε-amino group of lysine residues of histones.…”

Section: Introductionmentioning

confidence: 99%

KAT7 is a therapeutic vulnerability ofMLL-rearranged acute myeloid leukemia

Braekeleer

et al. 2020

Preprint

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Histone acetyltransferases (HATs) catalyze the transfer of an acetyl group from acetyl-CoA to lysine residues of histones and play a central role in transcriptional regulation in diverse biological processes. Dysregulation of HAT activity can lead to human diseases including developmental disorders and cancer. Through genome-wide CRISPR-Cas9 screens, we identified several HATs of the MYST family as fitness genes for acute myeloid leukaemia (AML). Here we investigate the essentiality of lysine acetyltransferase KAT7 in AMLs driven by the MLL-X gene fusions. We found that KAT7 loss leads to a rapid and complete loss of both H3K14ac and H4K12ac marks, in association with reduced proliferation, increased apoptosis and differentiation of AML cells. Acetyltransferase activity of KAT7 is essential for the proliferation of these cells. Mechanistically, our data propose that acetylated histones provide a platform for the recruitment of MLL-fusion-associated adaptor proteins such as BRD4 and AF4 to gene promoters. Upon KAT7 loss, these factors together with RNA polymerase II rapidly dissociate from several MLL-fusion target genes that are essential for AML cell proliferation, including MEIS1, PBX3 and SENP6. Our findings reveal that KAT7 is a plausible therapeutic target for this poor prognosis AML subtype.

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The many lives of KATs — detectors, integrators and modulators of the cellular environment

Cited by 140 publications

References 296 publications

Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele

KAT7 is a therapeutic vulnerability ofMLL-rearranged acute myeloid leukemia

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