Biology subjects

Abdulla, A. Z.

Publications and source records attributed to Abdulla, A. Z..

4 recordsLinked to original sources

bioRxiv2026

Feedback control via H3K9 methylation and siRNA biogenesis autonomously maintains RNAi heterochromatin through continuous low-level transcription

The logic of RNA-based silencing involves nascent RNA molecules that serve as scaffolds to recruit proteins that repress transcription. Despite transcription and silencing being antagonistic, RNA-based recruitment mechanisms have been widely adopted in organisms ranging from yeast to humans. In fission yeast (Schizosaccharomyces pombe), the nuclear RNAi pathway that establishes heterochromatin at pericentromeric repeats to silence transcription exemplifies this paradox. Current models propose that cells reconcile these opposing activities by confining pericentromeric transcription to S phase while maintaining silencing during the rest of the cell cycle. Here, using strand-specific single-molecule RNA FISH (smFISH), we detect forward and reverse pericentromeric transcripts with high sensitivity and single-cell resolution. We find that repeat-associated transcription is rare, heterogeneous and happens independently of cell-cycle control. Instead, transcript production is governed solely by feedback involving small RNA biogenesis and H3K9 methylation. By combining mathematical modeling with experiments, we show that low levels of H3K9me or siRNAs prevent heterochromatin establishment, whereas high levels of H3K9me cause stochastic switching. Our work reveals that the same RNA-based feedback architecture can sample distinct transcriptional regimes, with feedback strength determining how often cells produce transcripts without any external regulatory inputs.

molecular biology↗

bioRxiv2026

Nucleosome remodeling by a CHD enzyme promotes H3K9 methylation establishment and spreading via remodeler-writer feedback

In Schizosaccharomyces pombe, the conserved CHD remodeler Mit1 function within the SHREC remodeler-deacetylase complex (a homolog of the metazoan Mi-2/NuRD complex), which is essential for H3K9 methylation-dependent heterochromatin establishment. However, the mechanism by which remodeler activity promotes silencing is unknown. Current models posit a hierarchical relationship between histone modifications and remodeler activity, with Mit1 acting exclusively downstream of H3K9 methylation. Here, we challenge this model by showing that tethering Mit1 at an ectopic site within euchromatin is sufficient to initiate heterochromatin assembly and generate extended domains of de novo H3K9 methylation. This process requires the Mit1 catalytic activity but does not involve direct physical interaction with Clr4, suggesting Mit1-mediated nucleosome remodeling creates a chromatin context that enhances Clr4 function. Using a genome-wide deletion screen, we determined that Mit1-initiated silencing requires all core heterochromatin factors and is critically dependent on Clr4 dosage. Furthermore, Mit1 activity facilitates heterochromatin spreading at subtelomeric regions and promotes H3K9 methylation at novel genomic sites implicated in cellular adaptation. Together, our findings support a model in which remodeler-writer pairs, analogous to reader-writer pairs, constitute conserved regulatory modules through which nucleosome organization directs the establishment of heritable epigenetic states.

genetics↗

bioRxiv2023

Topological constraints and finite-size effects in quantitative polymer models of chromatin organization

Polymer physics simulations have provided a versatile framework to quantitatively explore the complex mechanisms driving chromosome organization. However, simulating whole chromosomes over biologically-relevant timescales at high resolution often constitutes a computationally-intensive task -- while genes or other regions of biological interest may typically only span a small fraction of the full chromosome length. Conversely, only simulating the sub-chromosomal region of interest might provide an over-simplistic or even wrong description of the mechanism controlling the 3D organization. In this work, we characterize what should be the minimal length of chromosome to be simulated in order to correctly capture the properties of a given restricted region. In particular, since the physics of long, topologically-constrained polymers may significantly deviate from those of shorter chains, we theoretically investigate how chromosomes being a long polymer quantitatively affects the structure and dynamics of its sub-segments. We show that increasing the total polymer length impacts on the topological constraints acting on the system and thus affects the compaction and mobility of sub-chains. Depending on the entanglement properties of the system, we derive a phenomenological relation defining the minimal total length to account for to maintain a correct topological regime. We finally detail the implications of these conclusions in the case of several specific biological systems. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/545312v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@2c8a4eorg.highwire.dtl.DTLVardef@2c1241org.highwire.dtl.DTLVardef@1628d64org.highwire.dtl.DTLVardef@130dd77_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory

In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of "reader-writer" enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of{gamma} H2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.

biophysics↗