Distinct developmental phenotypes result from mutation of Set8/KMT5A and histone H4 lysine 20 in <i>Drosophila melanogaster</i>

Crain, Aaron T.; Klusza, Stephen; Armstrong, Robin L.; Rosa, Priscila Santa; Temple, Brenda; Strahl, Brian D.; McKay, Daniel J.; Matera, A. Gregory; Duronio, Robert J.

doi:10.1101/2022.01.30.478405

Cited by 3 publications

(3 citation statements)

References 107 publications

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“…Therefore, the H4K20me1 mark at a global scale may show an association with reduced transcription, similar to its role in cell cycle regulation. While SETD8 is conserved in flies and humans, the enzyme and the target H4K20me1 have distinct roles in the eye development of Drosophila (Crain et al 2022). The transient decrease in the target mark in Hydra and the marked phenotype observed also point towards such a role in the Cnidarian.…”

Section: Discussionmentioning

confidence: 99%

“…5A). While SETD8 is conserved in flies and humans, the enzyme and the target H4K20me1 have distinct roles in the eye development of Drosophila (Crain et al 2022). The transient decrease in the target mark in Hydra and the marked phenotype observed also point towards such a role in the Cnidarian.…”

Section: H4k20me1 Is a Global Repression Associated Histone Modificationmentioning

confidence: 99%

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H4K20me1 plays a dual role in transcriptional regulation during regeneration and axis patterning ofHydra

Gungi

Pal

Saha

et al. 2022

Preprint

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The evolution of the first body axis in the animal kingdom and an extensive ability to regenerate makes Hydra, a Cnidarian, an excellent model system to understand the underlying epigenetic mechanisms. We identify that SETD8 is critical for regeneration, and H4K20me1 colocalizes with transcriptional activation machinery locally at the β-catenin bound TCF/LEF binding sites on the promoters of head-associated genes, marking an epigenetic activation node. Contrastingly, genome-wide analysis of the H4K20me1 occupancy revealed a negative correlation with transcriptional activation. We propose H4K20me1 as a general repressive histone mark in Cnidaria and describe its dichotomous role in transcriptional regulation in Hydra.

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Section: Discussionmentioning

confidence: 99%

Section: H4k20me1 Is a Global Repression Associated Histone Modificationmentioning

confidence: 99%

H4K20me1 plays a dual role in transcriptional regulation during regeneration and axis patterning ofHydra

Gungi

Pal

Saha

et al. 2022

Preprint

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“…One possibility is methylation of histone H4 lysine 20 (H4K20). Like H3K36me3 and H4K16ac, H4K20 monomethylation localizes preferentially to gene bodies [85][86][87]. In vitro studies demonstrate that H4K20me1 and H4K20me2 peptides have an up-28 to 50fold higher affinity for the MSL3 chromodomain compared to H3K36me3 [88][89][90].…”

Section: Trimethylation Of H3k36 Is Not Essential For Spreading Of Th...mentioning

confidence: 99%

Set2 and H3K36 regulate theDrosophilamale X chromosome in a context-specific manner, independent from MSL complex spreading

Salzler,

Vandadi,

Matera

2024

Preprint

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Dosage compensation in Drosophila involves upregulating male X-genes two-fold. This process is carried out by the MSL (male-specific lethal) complex, which binds high-affinity sites and spreads to surrounding genes. Current models of MSL spreading focus on interactions of MSL3 (male-specific lethal 3) with histone marks; in particular, Set2-dependent H3 lysine-36 trimethylation (H3K36me3). However, Set2 might affect DC via another target, or there could be redundancy between canonical H3.2 and variant H3.3 histones. Further, it is difficult to parse male-specific effects from those that are simply X-specific. To discriminate among these possibilities, we employed genomic approaches in H3K36 residue and Set2 writer mutants. The results confirm a role for Set2 in X-gene regulation, but show that expression trends in males are often mirrored in females. Instead of global, male-specific reduction of X-genes in Set2/H3K36 mutants, we observe heterogeneous effects. Interestingly, we identified cohorts of genes whose expression was significantly altered following loss of H3K36 or Set2, but changes were in opposite directions, suggesting that H3K36me states have reciprocal functions. In contrast to H4K16R controls, analysis of combined H3.2K36R/H3.3K36R mutants neither showed consistent reduction in X-gene expression, nor any correlation with MSL3 binding. Examination of other developmental stages/tissues revealed additional layers of context-dependence. Our studies implicate BEAF-32 and other insulator proteins in Set2/H3K36-dependent regulation. Overall, the data are inconsistent with the prevailing model wherein H3K36me3 directly recruits the MSL complex. We propose that Set2 and H3K36 support DC indirectly, via processes that are utilized by MSL but common to both sexes.

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Drosophila melanogasterSet8 and L(3)mbt function in gene expression independently of histone H4 lysine 20 methylation

Crain,

Butler,

Hill

et al. 2024

Preprint

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Mono-methylation of Lysine 20 of histone H4 (H4K20me1) is catalyzed by Set8 and thought to play important roles in many aspects of genome function that are mediated by H4K20me-binding proteins. We interrogated this model in a developing animal by comparing in parallel the transcriptomes ofSet8null,H4K20R/A, andl(3)mbtmutantDrosophila melanogaster. We found that the gene expression profiles ofH4K20AandH4K20Rlarvae are markedly different thanSet8nulllarvae despite similar reductions in H4K20me1.Set8nullmutant cells have a severely disrupted transcriptome and fail to proliferatein vivo, but these phenotypes are not recapitulated by mutation ofH4K20indicating that the developmental defects ofSet8nullanimals are largely due to H4K20me1-independent effects on gene expression. Further, the H4K20me1 binding protein L(3)mbt is recruited to the transcription start sites of most genes independently of H4K20me even though genes bound by L(3)mbt have high levels of H4K20me1. Moreover, both Set8 and L(3)mbt bind to purified H4K20R nucleosomesin vitro. We conclude that gene expression changes inSet8nullandH4K20mutants cannot be explained by loss of H4K20me1 or L(3)mbt binding to chromatin, and therefore that H4K20me1 does not play a large role in gene expression.

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Distinct developmental phenotypes result from mutation of Set8/KMT5A and histone H4 lysine 20 in Drosophila melanogaster

Cited by 3 publications

References 107 publications

H4K20me1 plays a dual role in transcriptional regulation during regeneration and axis patterning ofHydra

H4K20me1 plays a dual role in transcriptional regulation during regeneration and axis patterning ofHydra

Set2 and H3K36 regulate theDrosophilamale X chromosome in a context-specific manner, independent from MSL complex spreading

Drosophila melanogasterSet8 and L(3)mbt function in gene expression independently of histone H4 lysine 20 methylation

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