The importance of considering regulatory domains in genome-wide analyses – the nearest gene is often wrong!

Chua, Ellora Hui Zhen; Yasar, Samen; Harmston, Nathan

doi:10.1242/bio.059091

Cited by 14 publications

(7 citation statements)

References 133 publications

(153 reference statements)

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“…GREAT tool considers a gene regulatory domain definition that takes into account a basal regulatory domain in a minimum distance upstream and downstream of a gene TSS, which is extended up to 1 Mb [ 44 ]. This definition comes in agreement with the latest genome-wide experimental and computational data [ 61 , 62 , 63 , 64 , 65 ]. Collectively, the presence of HERVs in cCREs that are based in experimental data, suggest that HERV sequences may impact, in different degree, the epigenetic regulation of 4 out 5 human genes.…”

Section: Discussionsupporting

confidence: 86%

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

Μαρκόπουλος

2022

Diseases

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Human endogenous retroviruses (HERVs) are a family of endogenous retroviruses that comprise the ~8.93% of the human genome sequence, with a high proportion being human specific. The recent expansion of repeated HERV sequences has offered a framework for genetic and epigenetic innovation. In the current report, a systematic approach is implemented to catalogue regulatory elements within HERVs, as a roadmap to potential functions of HERV sequences in gene networks. ENCODE Project has offered a wealth of epigenetic data based on omics technologies. I analyzed the presence of HERV sequences on consensus cis-regulatory elements (cCREs) from ENCODE data. On the one side, HERVs are in 1 out of 9 cCREs (>100.000 cCREs in total), dispersed within the genome and present in cis-regulatory regions of ~81% of human genes, as calculated following gene enrichment analysis. On the other side, promoter-associated HERV cCREs are present adjacent to (in a 200 bp window) the transcription start sites of 256 human genes. Regulatory network production, followed by centrality analysis led to the discovery of 90 core genes containing HERV-associated promoters. Pathway analysis on the core network genes and their immediate neighbors revealed a regulatory footprint that, among others, is associated with inflammation, chemokine signaling and response to viral infection. Collectively, these results support the concept that the expansion of regulatory sequences derived from HERVs is critical for epigenetic innovation that may have wired together genes into novel transcriptional networks with critical roles in cellular physiology and pathology.

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Section: Discussionsupporting

confidence: 86%

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

Μαρκόπουλος

2022

Diseases

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“…Since the RA stimulus exerts its differentiating effect mainly through the members of the RA-activated nuclear receptors subfamily RAR (NR1B) that encompass 3 paralogs (i.e., RAR α , RAR β and RAR γ ), the annotation of the interaction edges linking the stimulus and the regulated genes was based on the presence/absence of ChIP-seq peaks for any RAR paralogs at less than 10 kb upstream or downstream of the annotated transcription start site (TSS) in RA-stimulated ES or EC cells [ 29 , 30 ]. Although arbitrary, the chosen distance between TSS and DNA binding site for the indicated transcription regulator is relatively conservative as transcriptional effect could be exerted from greater distance up to megabases [ 31 ] and the absence of supporting peak as defined should not be interpreted as a proof of absence of any direct modulating effect. Similarly, the edges supported by physical interactions data for Sox2 and Pou5f1, or Jarid2 were extracted from [ 32 , 33 ].…”

Section: Resultsmentioning

confidence: 99%

One model fits all: Combining inference and simulation of gene regulatory networks

et al. 2023

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The rise of single-cell data highlights the need for a nondeterministic view of gene expression, while offering new opportunities regarding gene regulatory network inference. We recently introduced two strategies that specifically exploit time-course data, where single-cell profiling is performed after a stimulus: HARISSA, a mechanistic network model with a highly efficient simulation procedure, and CARDAMOM, a scalable inference method seen as model calibration. Here, we combine the two approaches and show that the same model driven by transcriptional bursting can be used simultaneously as an inference tool, to reconstruct biologically relevant networks, and as a simulation tool, to generate realistic transcriptional profiles emerging from gene interactions. We verify that CARDAMOM quantitatively reconstructs causal links when the data is simulated from HARISSA, and demonstrate its performance on experimental data collected on in vitro differentiating mouse embryonic stem cells. Overall, this integrated strategy largely overcomes the limitations of disconnected inference and simulation.

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“…Similar findings have been reported in previous studies, where CRISPR-directed gene editing targeting exons resulted in exon skipping and alterations in gene expression (Banas et al, 2022). It is also known that different cell lines can have different transcriptional regulation mechanisms, and the regulatory regions of a gene may differ depending on the cell line being used (Kang et al, 2020;Chua et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Characterization of transcriptional enhancers in the chicken genome using CRISPR-mediated activation

Han,

Lee,

Kim

2023

Front. Genome Ed.

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DNA regulatory elements intricately control when, where, and how genes are activated. Therefore, understanding the function of these elements could unveil the complexity of the genetic regulation network. Genome-wide significant variants are predominantly found in non-coding regions of DNA, so comprehending the predicted functional regulatory elements is crucial for understanding the biological context of these genomic markers, which can be incorporated into breeding programs. The emergence of CRISPR technology has provided a powerful tool for studying non-coding regulatory elements in genomes. In this study, we leveraged epigenetic data from the Functional Annotation of Animal Genomes project to identify promoter and putative enhancer regions associated with three genes (HBBA, IRF7, and PPARG) in the chicken genome. To identify the enhancer regions, we designed guide RNAs targeting the promoter and candidate enhancer regions and utilized CRISPR activation (CRISPRa) with dCas9-p300 and dCas9-VPR as transcriptional activators in chicken DF-1 cells. By comparing the expression levels of target genes between the promoter activation and the co-activation of the promoter and putative enhancers, we were able to identify functional enhancers that exhibited augmented upregulation. In conclusion, our findings demonstrate the remarkable efficiency of CRISPRa in precisely manipulating the expression of endogenous genes by targeting regulatory elements in the chicken genome, highlighting its potential for functional validation of non-coding regions.

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The importance of considering regulatory domains in genome-wide analyses – the nearest gene is often wrong!

Cited by 14 publications

References 133 publications

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

One model fits all: Combining inference and simulation of gene regulatory networks

Characterization of transcriptional enhancers in the chicken genome using CRISPR-mediated activation

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