Biology subjects

Taher, L.

Publications and source records attributed to Taher, L..

9 recordsLinked to original sources

bioRxiv2026

Multi-layered characterization of ~700,000 conserved noncoding elements within the human genome

Conserved noncoding elements (CNEs) have been extensively studied for their roles as regulatory elements, particularly enhancers. However, the advent of technologies like ChIP-seq and ATAC-seq has shifted research focus away from comparative genomics. Here, we leveraged data from large-scale projects like ENCODE to address the resulting gap in the comprehensive functional characterization of CNEs. We first derived a set of [~]700,000 CNEs in the human genome from a 470-way mammalian alignment. Phylogenetic inference identified [~]670,000 conserved elements within primates and [~]240,000 conserved elements across mammals. Our functional genomic analysis revealed that, irrespective of their level of conservation, approximately one third of CNEs exhibit concurrent chromatin accessibility and H3K27 acetylation in at least one of 19 examined tissues and cell lines and thus, are likely to act as cis-regulatory elements. Extrapolating these data to additional tissues and cell lines suggested that [~]40% of the CNE repertoire possesses cis-regulatory potential. Moreover, we found that the 3D organization of CNEs is non-random; specifically, CNEs are preferentially located toward the centers of topologically associating domains. CNE co-activation networks derived from chromatin accessibility and active histone marks revealed that evolutionary constraints acting on CNEs functioning as cis-regulatory elements reflect not only their isolated individual role, but their topological context. To summarize, we have generated a novel catalog of CNEs annotated with empirical cis-regulatory evidence. While evolutionary constraint and regulatory function are clearly linked, a comprehensive understanding of their interplay remains elusive. This resource provides a foundation for exploring this relationship systematically. Significance statementPrevious studies have investigated conserved noncoding element (CNE) evolution, epigenomic landscapes, and 3D genome organization separately, yet a systematic framework integrating these dimensions has been lacking. Here, we identified [~]700,000 CNEs, including [~]240,000 CNEs deeply conserved across mammals, and show that a large fraction display enhancer-associated epigenomic signatures and are preferentially enriched within TAD centers, highlighting their regulatory relevance. By generating and analyzing this CNE catalog within an integrated evolutionary, epigenomic, and 3D genomic context, our study bridges a critical gap and provides a comprehensive resource to better understand regulatory architecture and its potential contribution to disease-associated variation.

evolutionary biology↗

bioRxiv2024

ENT3C: an entropy-based similarity measure for contact matrices

Hi-C and micro-C sequencing have shed light on the profound importance of 3D genome organization in cellular function by probing 3D contact frequencies across the linear genome. The resulting contact matrices are extremely sparse and susceptible to technical- and sequence-based biases, making their comparison challenging. The development of reliable, robust and efficient methods for quantifying similarity between contact matrix is crucial for investigating variations in the 3D genome organization between different cell types or under different conditions, as well as evaluating experimental reproducibility. We present a novel method, ENT3C, which measures the change in pattern complexity in the vicinity of contact matrix diagonals to quantify their similarity. ENT3C provides a robust, user-friendly Hi-C or micro-C contact matrix similarity metric and a characteristic entropy signal that can be used to gain detailed biological insights into 3D genome organization. Availabilityhttps://github.com/xX3N1A/ENT3C

bioinformatics↗

bioRxiv2023

Disregarding multimappers leads to biases in the functional assessment of NGS data

Standard ChIP-seq and RNA-seq processing pipelines typically disregard sequencing reads whose origin is ambiguous ("multimappers"). This usual practice has potentially important consequences for the functional interpretation of the data: genomic elements belonging to clusters composed of highly similar members are left unexplored. In particular, disregarding multimappers leads to the systematic underrepresentation in epigenetic studies of recently active transposons, such as AluYa5 and L1HS. Furthermore, this common strategy also has implications for transcriptomic analysis: members of repetitive gene families, such the ones including major histocompatibility complex (MHC) class I and II genes, are systematically underquantified. Based on these findings, we strongly advocate for the implementation of multimapper-aware bioinformatic genomic analyses.

genomics↗

bioRxiv2022

Predicting 3D genome architecture directly from the nucleotide sequence with DNA-DDA

3D genome architecture is characterized by multi-scale patterns and plays an essential role in gene regulation. Chromatin conformation capturing experiments have revealed many properties underlying 3D genome architecture such as the compartmentalization of chromatin based on transcriptional states. However, they are complex, costly, and time consuming, and therefore only a limited number of cell types have been examined using these techniques. Increasing effort is being directed towards deriving computational methods that can predict chromatin conformation and associated structures. Here we present DNA-DDA, a purely sequence-based method based on chaos theory to predict genome-wide A and B compartments. We show that DNA-DDA models derived from a 20 Mb sequence are sufficient to predict genome wide compartmentalization at the scale of 100 kb in four different cell types. Although this is a proof-of-concept study, our method shows promise in elucidating the mechanisms responsible for genome folding as well as modeling the impact of genetic variation on 3D genome architecture and the processes regulated thereby. Availabilityhttps://github.com/xX3N1A/DNA-DDA Contactleila.taher@tugraz.at Supplementary informationSupplementary data are available at ... online.

bioinformatics↗

bioRxiv2022

How enhancers regulate wavelike gene expression patterns: A novel enhancer prediction and live reporter system identifies an enhancer associated with the arrest of pair-rule waves in Tribolium

A key problem in development is to understand how genes turn on or off at the right place and right time during embryogenesis. Such decisions are made by non-coding sequences called enhancers. Much of our models of how enhancers work rely on the assumption that genes are activated de novo as stable domains across embryonic tissues. Such view has been strengthened by the intensive landmark studies of the early patterning of the anterior-posterior (AP) axis of the Drosophila embryo, where indeed gene expression domains seem to arise more or less stably. However, careful analysis of gene expressions in other model systems (including the AP patterning in vertebrates and short-germ insects like the beetle Tribolium castaneum) painted a different, very dynamic view of gene regulation, where genes are oftentimes expressed in a wavelike fashion. How such gene expression waves are mediated at the enhancer level is so far unclear. Here we establish the AP patterning of the short-germ beetle Tribolium as a model system to study dynamic and temporal pattern formation at the enhancer level. To that end, we established an enhancer prediction system in Tribolium based on time- and tissue-specific ATAC-seq and an enhancer live reporter system based on MS2 tagging. Using this experimental framework, we discovered several Tribolium enhancers, and assessed the spatiotemporal activities of some of them in live embryos. We found our data consistent with a model in which the timing of gene expression during embryonic pattern formation is mediated by a balancing act between enhancers that induce rapid changes in gene expressions (that we call dynamic enhancers) and enhancers that stabilizes gene expressions (that we call static enhancers).

developmental biology↗

bioRxiv2019

The presence of copy number variants in specific topologically associating domains has prognostic value in many cancer types

The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting interactions between regulatory elements, and their disruption by genomic rearrangements can result in altered gene expression and, ultimately, in cancer. Here, we provide a proof-of-principle that mutations within TADs can be used to predict the survival of cancer patients. For this purpose, we first constructed a set of 1,467 TADs representing the three-dimensional organization of genome across 24 normal human tissues. We then used Cox regression analysis to assess the prognostic value of the TADs in different cancer types, and identified a total of 35 TADs that were prognostic for at least one of nine cancer types. Interestingly, only 46% of the prognostic TADs comprised one or more genes with a known causal association with cancer. Moreover, for those TADs encompassing such a gene, the prognostic effect of the TAD was only directed related to the presence/absence of mutations in the gene in 13% of the cases. These observations indicate that the predictive power of a large proportion of the prognostic TADs is independent of whether pan-cancer genes are mutated or not. Furthermore, 34% of the 35 prognostic TADs showed strong structural perturbations in the cancer genome, which might mediate cancer development and progression. This study has important implications for the interpretation of cancer-related non-coding mutations and offer insights to new strategies for personalizing cancer medicine.

cancer biology↗

bioRxiv2019

Independent transposon exaptation is a widespread mechanism of shadow enhancer evolution in the mammalian genome

Many regulatory networks involve (possibly partially) redundant cis-regulatory elements. These elements are commonly referred to as shadow enhancers and have been assumed to mainly originate by sequence duplication. An alternative mechanism that has not been examined involves the independent exaptation of transposons. Here, we identified 2,117 and 2,787 pairs of shadow enhancers in the human and mouse genomes, respectively, and found that 34% and 18% of these pairs derive from transposons. Moreover, we show that virtually all the enhancer partners of these transposon-derived shadow enhancer pairs are independent exaptations from different transposon types and hypothesize that the increase in the expression and tissue-specificity of their targets as compared to those of non-shadow enhancers facilitates their fixation in the genome. Finally, we provide evidence that the regulatory redundancy observed in many mammalian regulatory networks is predominantly driven by convergent evolution, since shadow enhancers are hardly ever conserved across species.

genomics↗

bioRxiv2018

An integrated genome-wide multi-omics analysis of gene expression dynamics in the preimplantation mouse embryo

Early mouse embryos have an atypical translational machinery comprised of cytoplasmic lattices, poorly competent for translation. Thus, the impact of transcriptomic changes on the operational levels of proteins has likely been overestimated in the past. To find out, we used liquid chromatography-tandem mass spectrometry to detect and quantify 6,550 proteins in the oocyte and in six developmental stages (from zygote to blastocyst) collected in triplicates, and we also performed mRNA sequencing.\n\nIn contrast to the known split between the 2-cell and 4-cell stages at the transcript level, on the protein level the oocyte-to-embryo transition appeared to last until the morula stage. In general, protein abundance profiles were weakly correlated with those of their cognate mRNAs and we found little or no concordance between changes in protein and transcript expression relative to the oocyte at early stages. However, concordance increased towards morula and blastocyst, hinting at a more direct coupling of proteins with transcripts at these stages, in agreement with the increase in free ribosome abundance. Independent validation by immunofluorescence and qPCR confirmed the existence of genes featuring strongly positively and negatively correlated protein and transcript. Moreover, consistent coverage of most known protein complexes indicates that our dataset represents a large fraction of the expressed proteome. Finally, we identified 20 markers, including members of the endoplasmic reticulum pathway, for discriminating between early and late stages.\n\nThis resource contributes towards closing the gap between the predicted phenotype, based on mRNA, and the actual phenotype, based on protein, of the mouse embryo.

developmental biology↗

bioRxiv2018

Genomic Analysis of a Transcriptional Networks Directing Progression of Cell States During MGE development.

BackgroundHomeodomain (HD) transcription factor (TF) NKX2-1 critical for the regional specification of the medial ganglionic eminence (MGE) as well as promoting the GABAergic and cholinergic neuron fates via the induction of TFs such as LHX6 and LHX8. NKX2-1 defines MGE regional identity in large part through transcriptional repression, while specification and maturation of GABAergic and cholinergic fates is mediated in part by transcriptional activation via TFs such as LHX6 and LHX8. Here we analyze the signaling and TF pathways, downstream of NKX2-1, required for GABAergic and cholinergic neuron fate maturation.\n\nMethodsDifferential ChIP-seq analysis was used to identify regulatory elements (REs) where chromatin state was sensitive to change in the Nkx2-1cKO MGE at embryonic day (E) 13.5. TF motifs in the REs were identified using RSAT. CRISPR-mediated genome editing was used to generate enhancer knockouts. Differential gene expression in these knockouts was analyzed through RT-qPCR and in situ hybridization. Functional analysis of motifs within hs623 was analyzed via site directed mutagenesis and reporter assays in primary MGE cultures.\n\nResultsWe identified 4782 activating REs (aREs) and 6391 repressing REs (rREs) in the Nkx2-1 conditional knockout (Nkx2-1cKO) MGE. aREs are associated with basic-Helix-Loop-Helix (bHLH) TFs. Deletion of hs623, an intragenic Tcf12 aRE, caused a reduction of Tcf12 expression in the sub-ventricular zone (SVZ) and mantle zone (MZ) of the MGE. Mutation of LHX, SOX and octamers, within hs623, caused a reduction of hs623 activity in MGE primary cultures.\n\nConclusionsTcf12 expression in the sub-ventricular zone (SVZ) of the MGE is mediated through aRE hs623. The activity of hs623 is dependent on LHX6, SOX and octamers. Thus, maintaining the expression of Tcf12 in the SVZ involves on TF pathways parallel and genetically downstream of NKX2-1.

developmental biology↗