Biology subjects

Bandau, S.

Publications and source records attributed to Bandau, S..

5 recordsLinked to original sources

bioRxiv2026

DNA methylation links lagging strand replication to transposable element control

DNA methylation is an essential epigenetic mark that silences transposable elements (TEs) in mammalian genomes1,2. Following DNA replication, methylation patterns must be faithfully restored3,4, yet how the two processes are coordinated remains unclear. Here, using strand-specific, genome-wide analyses5-7 in mouse embryonic stem cells, we show that DNA methylation maintenance is coupled to the lagging-strand synthesis in TE-rich regions. Paradoxically, despite this targeting, the lagging strand is more permissive for TE integration than the leading strand. Notably, insertions of full-length LINE-1s, SINEs, and satellite repeats are all enriched on the lagging strand over evolutionary time. Consequently, most TEs, particularly young elements, are oriented head-on relative to replication forks in the mouse genome, creating an unfavorable genomic configuration8 that is preferentially targeted by DNA methylation maintenance. Mechanistically, DNA methylation maintenance is coupled to the lagging-strand replication via UHRF1-LIG19 and PCNA-PAF1510 interactions, and the interference in this mechanism slows Okazaki fragment maturation, and thereby potentially may facilitate TE retention. Together, we show a mechanism of TE control during DNA replication with an unexpected evolutionary interplay in which DNA methylation may facilitate, rather than solely prevent, TE expansion.

Molecular Biology↗

bioRxiv2026

Chromatin assembly at replication forks enables differentiation of human iPSCs

DNA replication is both productive and disruptive, synthesising new DNA while dismantling chromatin to allow fork progression. Because of its disruptive nature, DNA replication has been suggested to enable chromatin changes facilitating cell fate transitions. However, the role of DNA replication in cell fate transitions remains incompletely understood. Here we show that upon differentiation of human induced Pluripotent Stem Cells (iPSCs) into presomitic mesoderm, DNA replication allows hundreds of proteins, including transcription factors, histone chaperones, and histone methyltransferases, to access chromatin. Moreover, H3K9 methylation is enhanced upon differentiation through a DNA replication-coupled process. Most of the proteins recruited to (or evicted from) nascent chromatin during differentiation are already present in iPSCs, suggesting they may play a role in the early response to differentiation. Among these, we identified ERH and SETDB1 as essential for mesoderm differentiation. Our work reveals a new paradigm to explore: how differentiation signals exploit the replisome interactome to enable rapid chromatin changes.

cell biology↗

bioRxiv2025

RIF1 orchestrates a multi-step restoration of post-replicative H3K9me3

DNA replication causes the dilution of parental histones along with their specific post-translational modifications. The kinetics of restoring these marks on newly incorporated histones dictate how quickly genomic domains regain their epigenetic identity after replication. H3K9me3 is restored extremely slowly; the process of reconstitution, to achieve the pre-replication levels, continues throughout the following G1 phase. The molecular mechanisms behind this slow reconstitution are unknown. We show here that RIF1s reassociation with heterochromatin during mitotic exit is required to set up a chromatin environment permissive for histone methyltransferases to resume H3K9me3 deposition. RIF1 facilitates the recruitment of SUV39H1, HP1 and HP1{beta} and is required for the increased tri-methylation of H3K9 that occurs during G1 phase. RIF1 is also indispensable for recruiting Protein Phosphatase 1 (PP1) to heterochromatin, and the interaction between RIF1 and PP1 is essential for the maintenance of H3K9me3 levels. In addition, RIF1-PP1 complex temporally restrains the activity of Aurora kinase at heterochromatin, ensuring that phosphorylation of H3S10 does not precede replication. This creates a time- window permissive for SUV39Hs to initiate the reinstatement of H3K9me3.

cell biology↗

bioRxiv2023

Transcription promotes the restoration of chromatin following DNA replication.

DNA replication results in the transient eviction of nucleosomes, RNAPII and transcription regulators. How chromatin organization is duplicated on the two daughter strands is a central question in epigenetics. In mammals, transcription restarts on newly replicated DNA within a couple of hours, promoting chromatin accessibility. However, the role of transcription in the restoration of other chromatin determinants following DNA replication remains unclear. Here we have monitored protein re-association to newly replicated DNA upon inhibition of transcription using iPOND coupled to quantitative mass spectrometry. We show that nucleosome assembly and the re-establishment of most histone modifications are uncoupled from transcription restart. However, upon transcription inhibition, the re-association of many proteins was altered, including ATP-dependent remodellers, transcription regulators, the histone variant H2A.Z, histone modifiers as well as the restoration of H3.3K36me2. Finally, transcription also provoked the recruitment of several DNA repair proteins, revealing that transcription promotes chromatin reestablishment post-replication but is also a potential source of genotoxic stress.

molecular biology↗

bioRxiv2020

FAM111A regulates replication origin activation and cell fitness

FAM111A is a replisome associated protein and dominant mutations within its trypsin-like peptidase domain are linked to severe human developmental syndromes. However, FAM111A functions and its putative substrates remain largely unknown. Here, we showed that FAM111A promotes origin activation and interacts with the putative peptidase FAM111B, and we identified the first potential FAM111A substrate, the suicide enzyme HMCES. Moreover, unrestrained expression of FAM111A wild-type and patient mutants impaired DNA replication and caused cell death only when the peptidase domain remained intact. Altogether our data reveal how FAM111A promotes DNA replication in normal conditions and becomes harmful in a disease context.

molecular biology↗