Biology subjects

Chevallier, O.

Publications and source records attributed to Chevallier, O..

7 recordsLinked to original sources

bioRxiv2023

Mitotic chromatin marking governs asymmetric segregation of DNA damage

The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serine residues. Functionally, this chromatin-marking pathway drives the asymmetric segregation of UV damage in the cell progeny with consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.

molecular biology↗

bioRxiv2022

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

Pediatric high-grade gliomas (pHGG) are devastating and incurable brain tumors with recurrent mutations in histone H3.3. These mutations promote oncogenesis by dysregulating gene expression through alterations of histone modifications. We identify aberrant DNA repair as an independent oncogenic mechanism, which fosters genome instability and tumor cell growth in H3.3 mutant pHGG, thus opening new therapeutic options. The two most frequent H3.3 mutations in pHGG, K27M and G34R, drive aberrant repair of replication-associated damage by non-homologous end joining (NHEJ). Aberrant NHEJ is mediated by the DNA repair enzyme Polynucleotide Kinase 3-Phosphatase (PNKP), which shows increased association with mutant H3.3 at damaged replication forks. PNKP sustains the proliferation of cells bearing H3.3 mutations, thus conferring a molecular vulnerability, specific to mutant cells, with potential for therapeutic targeting.

cancer biology↗

bioRxiv2020

Dissecting regulatory pathways for transcription recovery following DNA damage reveals a non-canonical function of the histone chaperone HIRA

Transcription restart after a genotoxic challenge is a fundamental yet poorly understood process. Here, we dissect the interplay between transcription and chromatin restoration after DNA damage by focusing on the human histone chaperone complex HIRA, which is required for transcription recovery post UV. We demonstrate that HIRA is recruited to UV-damaged chromatin via the ubiquitin-dependent segregase VCP to deposit new H3.3 histones. However, this local activity of HIRA is dispensable for transcription recovery. Instead, we reveal a genome-wide function of HIRA in transcription restart that is independent of new H3.3 and not restricted to UV-damaged loci. HIRA coordinates with ASF1B to control transcription restart by two independent pathways: by stabilizing the associated subunit UBN2 and by reducing the expression of the transcription repressor ATF3. Thus, HIRA primes UV-damaged chromatin for transcription restart at least in part by relieving transcription inhibition rather than by depositing new H3.3 as an activating bookmark.

molecular biology↗

bioRxiv2019

Histone chaperones and modifiers cooperate to maintain heterochromatin integrity following DNA damage.

Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV, SETDB1 coordinating histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.

molecular biology↗

bioRxiv2018

Comparison of tri-exponential decay vs. bi-exponential decay and full fitting vs. segmented fitting for modeling liver intravoxel incoherent motion diffusion MRI

PurposeTo determine whether bi- or tri-exponential models, and full or segmented fittings, better fit IVIM imaging signal of healthy livers.\n\nMaterials and methodsDiffusion-weighted images were acquired with a 3-T scanner using respiratory-triggered echo-planar sequence and 16 b-values (0[~]800 s/mm2). Eighteen healthy volunteers had liver scanned twice in the same session, and then once again in another session. Region of interest (ROI)-based measurements were processed with bi-exponential model full fitting and segmented fitting (threshold b-value = 80 s/mm2), as well as tri-exponential model full fitting and segmented fitting (threshold b-value = 200 s/mm2).\n\nResultsWith all scans signal averaged, bi-exponential model full fitting showed Dslow=1.14, Dfast=193.6x10-3 mm2/s, and PF=16.9%, and segmented fitting showed Dslow=1.03, Dfast=56.7x10-3 mm2/s, and PF=21.3%. IVIM parameters derived from tri-exponential model were similar for full fitting and segmented fitting, with a slow (Dslow=0.98x10-3 mm2/s; Fslow=76.4 or 76.6%), a fast (Dfast=15.1 or 15.4x10-3 mm2/s; Ffast=11.8 or 11.7%) and a very fast (DVfast=445.0 or 448.8x10-3 mm2/s; FVfast=11.8 or 11.7 %) diffusion compartments. Tri-exponential model provided an overall better fit than bi-exponential model. For bi-exponential model, full fitting provided better fit at very low and low b-values compared with segmented fitting with the later tended to underestimate Dfast, however, segmented method demonstrated lower error in signal prediction for high b-values. Compared with full fitting, tri-exponential segmented fitting offered better scan-rescan reproducibility.\n\nConclusionFor healthy liver, tri-exponential modelling is preferred than bi-exponential modelling. For bi-exponential model, segmented fitting underestimates Dfast, but offers more accurate estimation of Dslow.

biophysics↗

bioRxiv2018

The histone chaperones FACT and ANP32E reshape the chromatin landscape during DNA damage repair through H2A.Z/H2A.X histone variant exchange

Safeguarding cell function and identity following a genotoxic stress challenge entails a tight coordination of DNA damage signaling and repair with chromatin maintenance. How this coordination is achieved and with what impact on chromatin integrity remains elusive. Here, by investigating the mechanisms governing the distribution of H2A.X in mammalian chromatin, we demonstrate that this histone variant is deposited de novo at sites of DNA damage in a repair synthesis-coupled manner. Our mechanistic studies further identify the histone chaperone FACT (Facilitates Chromatin Transcription) as responsible for the deposition of newly synthesized H2A.X. Functionally, FACT potentiates H2A.X-dependent signaling of DNA damage and, together with ANP32E (Acidic Nuclear Phosphoprotein 32 Family Member E), orchestrates a H2A.Z/H2A.X exchange reaction that reshapes the chromatin landscape at repair sites. We propose that this mechanism promotes chromatin accessibility and helps tailoring DNA damage signaling to repair progression.\n\nHIGHLIGHTSO_LIH2A.X, but not H2A.Z, is deposited de novo at sites of DNA damage repair\nC_LIO_LIFACT promotes new H2A.X deposition coupled to repair synthesis\nC_LIO_LIFACT and ANP32E chaperones orchestrate H2A.Z/H2A.X exchange in damaged chromatin\nC_LIO_LIFACT stimulates H2A.X-dependent signaling of DNA damage\nC_LI

molecular biology↗

bioRxiv2017

IVIM parameters have good scan-rescan reproducibility when evidential motion contaminated and poorly fitted image data are removed

BackgroundIntravoxel Incoherent Motion (IVIM) diffusion MRI is a promising technique for liver pathology evaluation, but this techniques scan-rescan reproducibility has been reported to be unsatisfactory.\n\nObjectiveTo understand whether IVIM MRI parameters for liver parenchyma can be good after removal of motion contaminated and/or poorly fitted image data.\n\nMaterial and MethodsEighteen healthy volunteers had liver scanned twice at the same session to assess scan-rescan repeatability, and again in another session after an average interval of 13 days to assess reproducibility. Diffusion weighted image were acquired with a 3T scanner using respiratory-triggered echo-planar sequence and 16 b-values (0 to 800 s/mm2). Measurement was performed on the right liver with segmented-unconstrained least square fitting. Image series with evidential anatomical mismatch, apparent artifacts, and poorly fitted signal intensity vs. b-value curve were excluded. A minimum of three slices was deemed necessary for IVIM parameter estimation of a liver.\n\nResultsWith total 54 examinations, 6 scans did not satisfy inclusion criteria, leading to a success rate of 89%; and 14 volunteers were finally included. With each scan a mean of 5.3 slices (range: 3-10 slices) were utilized for analysis. Using threshold b-value=80s/mm2, the coefficient of variation and within-subject coefficient of variation for repeatability and reproducibility were: 2.86% and 4.24% for Dslow, 3.81% and 4.24%, for PF, 18.16% and 24.88% for Dfast; and those for reproducibility were 2.48% and 3.24% for Dslow; 4.91% and 5.38% for PF; 21.18% and 30.89% for Dfast.\n\nConclusionIVIM parameter scan-rescan reproducibility can be potentially good.

biophysics↗