Biology subjects

Boulet, F.

Publications and source records attributed to Boulet, F..

4 recordsLinked to original sources

bioRxiv2026

Explainable AI identifies H3K18ac as a new marker of active enhancers

Enhancers are non-coding regions of DNA that regulate gene transcription, yet the mechanisms underlying enhancer activity remain incompletely understood. Despite extensive experimental and computational efforts, we still lack accurate enhancer maps in many human cells, tissues and disease contexts. Here, we developed several Artificial Intelligence (AI) models (Convolutional Neural Networks (CNN), XGBoost, Logistic Regression (LR) and an eXplainable Artificial Intelligence type2 Fuzzy Logic based System (type2-FLS)) to predict enhancers across different human and mouse cell lines. While all models display high accuracy in the cell lines they were trained on, our results confirmed that type2-FLS, and, partially, CNN, LR and XGBoost perform consistently well in cell lines unseen during training, supporting the generalisation of the models. Most importantly, type2-FLS identified H3K18ac as an important enhancer mark along with many novel putative enhancers, which display the same epigenetic signatures as experimentally identified ones. We have validated some of these novel enhancers by both global epigenetic perturbations and directed enhancer epigenetic rewriting (CRISPRi). Interestingly, seven epigenetic marks in humans and five in mouse are sufficient to annotate enhancers without losing accuracy. Overall, we have deciphered the epigenetic code of mammalian enhancers and annotated enhancers in multiple human and mouse cell lines.

genomics↗

bioRxiv2026

BRD4 represses developmental and neuronal genes through interactions with polycomb complexes

BRD4 is best known as a transcriptional co-activator, yet heterozygous loss-of-function variants cause craniofacial and neurodevelopmental abnormalities through unclear mechanisms. Using human embryonic stem cells and neural organoids as an in vitro model of human embryonic brain development, we show that BRD4 represses polycomb-regulated developmental and neuronal genes. BRD4 co-occupies bivalent promoters with PRC1.6 and directly interacts with PCGF6 and RING1B through its C-terminal domain. H3K23ac contributes to BRD4 recruitment through BD2, linking acetylated chromatin recognition to polycomb-associated repression. Acute BRD4 depletion alters PRC1.6 occupancy, reduces ubiquitination of H2AK119 and rapidly increases developmental gene transcription. In neural organoids, BRD4 BD2 mutations alter neuronal cell composition and increase expression and chromatin accessibility associated with neuronal transcription-factor programmes. These findings establish BRD4 as a context-dependent chromatin regulator that prevents premature activation of developmental genes and provide mechanistic insight into BRD4-associated neurodevelopmental disorders.

molecular biology↗

bioRxiv2024

Early Prediction of Preeclampsia Based on Transposable Elements signature in cell-free RNA

Preeclampsia (PE) is a pregnancy-associated hypertension disorder affecting 5-10% of pregnant women each year worldwide, which leads to adverse maternal and child outcomes. PE remains inadequately predicted, prevented and treated. Here, we comprehensively investigated altered transcriptomic and epigenetic changes in the PE placenta and maternal cell-free RNA (cfRNA). We show that many transposable elements (TEs) in sub-families are deregulated in the gestational age-matched PE placenta. Increased expression of endogenous retrovirus (ERV) and long interspersed nuclear element 1 (L1, LINE1) subfamilies of TEs is associated with higher histone acetylation levels at their regulatory elements. A higher TE transcript level correlates with the type I interferon (IFN-I) pathway, suggesting inflammation associated with PE could be due to the sensing of TE transcripts by the antiviral innate immune system. Consistent with higher TE transcript levels in the PE placentas, analysis of maternal cfRNA data revealed differential levels of TE subfamilies in PE compared to healthy controls. Machine learning-based training for TE transcripts for early prediction of PE showed a robust performance in the validation cohort, with an area under the curve (AUC) of 0.88, 81% sensitivity, and 74% positive predictive value (PPV). Overall, we show TE deregulation in the placenta is associated with PE, and maternal cfRNA TE signature accurately predicts early diagnosis of PE, which can improve prophylaxis and obstetric outcomes.

genomics↗

bioRxiv2022

H4K16ac activates transcription of transposable elements and contribute to their cis regulatory function

Mammalian genomes harbour a large number of transposable elements (TEs) and their remnants. Many epigenetic repression mechanisms are known to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here we demonstrated that the male-specific lethal (MSL) complex mediated acetylation of histone H4 lysine 16 (H4K16ac) activates transcription of long interspersed nuclear elements (LINE1, L1) and long terminal repeats (LTRs). Furthermore, we show that the H4K16ac marked L1 and LTR subfamilies function as enhancers and are enriched with chromatin features associated with active enhancers and looping factors. L1 and LTRs enriched with histone acetylations are bound by chromatin looping factors and these regions loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac marked L1s and LTRs regulate the expression of genes in cis. Overall, TEs enriched with H4K16ac contribute to the cis-regulatory landscape of a significant portion of the mammalian genome by maintaining an active chromatin landscape at TEs. One Sentence SummaryH4K16ac activates LINE1 and ERV/LTR transcription and rewires the cis-regulatory landscape of a significant portion of the mammalian genome by increasing the transcriptional activity at TEs.

genomics↗