Biology subjects

Barsoum, M.

Publications and source records attributed to Barsoum, M..

4 recordsLinked to original sources

bioRxiv2026

Reversing PROTAC-induced ASH2L degradation reactivates proliferation in senescent cells

Nucleosomes control access to gene promoters. Histone H3 lysine 4 tri-methylation, catalyzed by 6 KMT2 complexes, correlates with accessible promoters and gene expression. The catalytic activity of KMT2 enzymes depends on an obligatory core complex with ASH2L being an essential subunit. We find that PROTAC induced depletion of ASH2L reduces H3K4me3, deregulates gene expression and prevents proliferation. Upon prolonged ASH2L loss, cells develop a senescent phenotype, a process linked to aging and disease. Competing the PROTAC reactivates ASH2L, reestablishes H3K4me3 at promoters and reverts gene expression changes. Cells reenter the cell cycle and resume proliferation, thereby reverting senescence. Structure-function studies demonstrate that these molecular and cellular consequences are primarily due to the loss of ASH2L functions associated with KMT2 complexes. Together, these findings indicate that stress inflicted by the loss of KMT2 catalytic activities promotes a reversible senescence phenotype, suggesting that the functions of KMT2 complexes are implicated in aging. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/722411v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@10ace2forg.highwire.dtl.DTLVardef@667c81org.highwire.dtl.DTLVardef@78039dorg.highwire.dtl.DTLVardef@13563be_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Induction of senescence upon loss of the Ash2l core subunit of H3K4 methyltransferase complexes

Gene expression is controlled in part by post-translational modifications of core histones. Methylation of lysine 4 of histone H3 (H3K4), associated with open chromatin and gene transcription, is catalyzed by type 2 lysine methyltransferase complexes that require WDR5, RBBP5, ASH2L and DPY30 as core subunits. Ash2l is essential during embryogenesis and for maintaining adult tissues. To expand on the mechanistic understanding of Ash2l, we generated mouse embryo fibroblasts (MEFs) with conditional Ash2l alleles. Upon loss of Ash2l, methylation of H3K4 and gene expression were downregulated, which correlated with inhibition of proliferation and cell cycle progression. Moreover, we observed induction of senescence concomitant with a set of downregulated signature genes but independent of SASP. Many of the signature genes are FoxM1 responsive. Indeed, exogenous FOXM1 was sufficient to delay senescence. Thus, although the loss of Ash2l in MEFs has broad and complex consequences, a distinct set of downregulated genes promotes senescence.

cell biology↗

bioRxiv2021

A fungal plant pathogen overcomes conserved broad-spectrum disease resistance by rapid gene loss

Hosts and pathogens typically engage in a co-evolutionary arms race. This also applies to phytopathogenic powdery mildew fungi, which can rapidly overcome plant resistance and perform host jumps. Using experimental evolution, we show that the powdery mildew pathogen Blumeria hordei is capable of breaking the agriculturally important broad-spectrum resistance conditioned by barley loss-of-function mlo mutants. Partial mlo virulence of evolved B. hordei isolates is correlated with a distinctive pattern of adaptive mutations, including small-sized (8-40 kb) deletions, of which one is linked to the de novo insertion of a transposable element. Occurrence of the mutations is associated with a transcriptional induction of effector proteinencoding genes that is absent in mlo-avirulent isolates on mlo mutant plants. The detected mutational spectrum comprises the same loci in at least two independently isolated mlo-virulent isolates, indicating convergent multigenic evolution. The mutational events emerged in part early (within the first five asexual generations) during experimental evolution, likely generating a founder population in which incipient mlo virulence was later stabilized by additional events. This work highlights the rapid dynamic genome evolution of an obligate biotrophic plant pathogen with a transposon-enriched genome.

plant biology↗

bioRxiv2018

Gene erosion and genome expansion in a group of highly host-specialized fungal phytopathogens

Due to their comparatively small genome size and short generation time, fungi are exquisite model systems to study eukaryotic genome evolution. Powdery mildew (PM) fungi present an exceptional case where their strict host dependency (a lifestyle termed obligate biotrophy) is associated with some of the largest fungal genomes sequenced so far (>100 Mbp). This size expansion is largely due to the pervasiveness of transposable elements (TEs), which can cover more than 70% of these genomes, and is associated with the loss of multiple conserved ascomycete genes (CAGs) required for a free-living lifestyle. To date, little is known about the mechanisms that drove this expansion, and information on ancestral PM genomes is lacking. We report the genome analysis of the early-diverged PM species Parauncinula polyspora that in contrast to most other PMs reproduces exclusively sexually. The P. polyspora genome is surprisingly small (<30 Mb) and sparsely equipped with TEs (<10%), despite the conserved absence of a common defense mechanism (RIP) involved in constraining repetitive elements. The genome still harbors the majority of the CAGs that are absent in the genomes of the recently evolved PMs. We speculate that TE spread might have been limited by its unique reproduction strategy and host features and further hypothesize that the loss of CAGs may promote the evolutionary isolation and host niche specialization of PM fungi. Limitations associated with this evolutionary trajectory might have been in part counteracted by the evolution of plastic, TE-rich genomes and/or the expansion of gene families encoding secreted virulence proteins.

genomics↗