Chromatin domains and structure

The human genome is incredibly big - over two meters long. It must fold up to fit inside the nucleus that is a few microns in size. What do we know about this folding is that at the smallest scale 200 bp of DNA wraps around the histone octamer and forms 10 nm fiber. The nucleosome particle is known to be a structural and functional chromatin unit. The further folding processes are more mysterious and there is no common view on the further chromatin configuration. One common hypothesis suggests that 10-nm fiber folds into more compact 30-nm fiber that forms solenoidal or zigzag like structures. Another notion relying on the chromatin sédimentation, the fluorescence microscopy and the more recent studies such as the chromosome conformation capture postulâtes that the genome is organized into domains. Apart from the structural organization and folding, the genome has to be functional and topology emerged to be a key player in the genome functions. Recent studies have shown the importance of the long-range interactions and the genome-wide studies have revealed the universal nature of such regulatory genome topology interactions in the gene régulation. Looping interactions between sequences separated greatly in the linear genome have emerged to be the key mechanism of the gene régulation. Aiming to make one step closer to understanding the tight relationship between the chromatin structure and its function; discern the effect of genetic variability on function and structure of the human genome and follow the heritability of the genome spatial organization I was involved in two orthogonal projects. The first one is mainly focused on the genome 3D organization in Yoruban family of father, mother and daughter and the second, where we unravel how genetic variations perturb regulatory interactions within a dataset that combines the activity of regulatory elements, gene expression and genetic variations across 317 individuals. -- Le génome humain est immense et mesure plus de deux mètres de long. Il doit se replier afin de s'insérer à l'intérieur du noyau, qui lui ne mesure que quelques microns. Concernant le repliement, nous savons qu'à l'échellé la plus petite, environ 200 paires de base d'ADN entourent l'octamère d'histone et forme un filament de 10 nm. Le nucléosome forme l'unité de base structurelle et fonctionnelle de la chromatine. Cependant, les niveaux d'organisation supérieurs demeurent plus mystérieux et il n'y a pas de théorie universelle sur la configuration de la chromatine. Une hypothèse commune suggère que le filament de 10 nm se compacte en fibre de 30 nm qui forme des structures de type solénoïde ou de type zig zag. Un autre modèle basé sur la sédimentation de la chromatine et la microscopie à fluorescence postule que le génome est organisé en domaines. Outre l'organisation structurelle et le repliement, le génome doit être fonctionnel et la topologie est apparue comme un acteur majeur des fonctions génomiques. Des études récentes ont montré l'importance des interactions à longue distance et des études pangénomiques ont révélé la nature universelle de telles interactions topologiques dans la régulation des gènes. Les structures en boucle permettent l'interaction entre des séquences très éloignées dans un génome linéaire et sont maintenant reconnues comme étant un mécanisme clé de la régulation génique. Afin d'améliorer la compréhension de la relation étroite entre la structure de la chromatine et sa fonction, de déterminer l'effet de la variabilité génétique sur la fonction et la structure du génome humain ainsi que d'étudier l'héritabilité de l'organisation spatiale du génome, nous avons débuté deux projets en parallèle. Le premier est centré sur l'organisation génomique 3D au sein d'une famille Yoruba composée du père, de la mère et de la fille. Dans le second, nous tentons de découvrir comment les variations génétiques perturbent les interactions régulatrices à l'aide d'un ensemble de données combinant l'activité des éléments régulateurs, l'expression génique et les variations génétiques de 317 individus

Non-cell-autonomous disruption of nuclear architecture as a potential cause of COVID-19-induced anosmia

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell-autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters, SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (ORs) and of their signaling components. This non-cell-autonomous effect is preceded by a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic compartments harboring OR genes. Our data provide a potential mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, offering insight to its systemic effects in olfaction and beyond

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes.

peer reviewedCopy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.Molecular Psychiatry advance online publication, 31 May 2016; doi:10.1038/mp.2016.84

A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs

A potential contributory role for ciliary dysfunction in the 16p11.2 600 kb BP4-BP5 pathology

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved

Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts’ maps could uncover functionally and clinically related genes