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Article ; Online: Mosaic cis-regulatory evolution drives transcriptional partitioning of HERVH endogenous retrovirus in the human embryo

Thomas A Carter / Manvendra Singh / Gabrijela Dumbović / Jason D Chobirko / John L Rinn / Cédric Feschotte

eLife, Vol

2022 Volume 11

Abstract: The human endogenous retrovirus type-H (HERVH) family is expressed in the preimplantation embryo. A subset of these elements are specifically transcribed in pluripotent stem cells where they appear to exert regulatory activities promoting self-renewal ... ...

Abstract	The human endogenous retrovirus type-H (HERVH) family is expressed in the preimplantation embryo. A subset of these elements are specifically transcribed in pluripotent stem cells where they appear to exert regulatory activities promoting self-renewal and pluripotency. How HERVH elements achieve such transcriptional specificity remains poorly understood. To uncover the sequence features underlying HERVH transcriptional activity, we performed a phyloregulatory analysis of the long terminal repeats (LTR7) of the HERVH family, which harbor its promoter, using a wealth of regulatory genomics data. We found that the family includes at least eight previously unrecognized subfamilies that have been active at different timepoints in primate evolution and display distinct expression patterns during human embryonic development. Notably, nearly all HERVH elements transcribed in ESCs belong to one of the youngest subfamilies we dubbed LTR7up. LTR7 sequence evolution was driven by a mixture of mutational processes, including point mutations, duplications, and multiple recombination events between subfamilies, that led to transcription factor binding motif modules characteristic of each subfamily. Using a reporter assay, we show that one such motif, a predicted SOX2/3 binding site unique to LTR7up, is essential for robust promoter activity in induced pluripotent stem cells. Together these findings illuminate the mechanisms by which HERVH diversified its expression pattern during evolution to colonize distinct cellular niches within the human embryo.
Keywords	endogenous retroviruses ; genomics ; primate evolution ; embryonic stem cells ; HERVH ; transposable elements ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: “Cat’s Cradling” the 3D Genome by the Act of LncRNA Transcription

Melé, Marta / John L. Rinn

Molecular cell. 2016 June 02, v. 62, no. 5

2016

Abstract: There is growing evidence that transcription and nuclear organization are tightly linked. Yet, whether transcription of thousands of long noncoding RNAs (lncRNAs) could play a role in this packaging process remains elusive. Although some lncRNAs have ... ...

Abstract	There is growing evidence that transcription and nuclear organization are tightly linked. Yet, whether transcription of thousands of long noncoding RNAs (lncRNAs) could play a role in this packaging process remains elusive. Although some lncRNAs have been found to have clear roles in nuclear architecture (e.g., FIRRE, NEAT1, XIST, and others), the vast majority remain poorly understood. In this Perspective, we highlight how the act of transcription can affect nuclear architecture. We synthesize several recent findings into a proposed model where the transcription of lncRNAs can serve as guide-posts for shaping genome organization. This model is similar to the game “cat’s cradle,” where the shape of a string is successively changed by opening up new sites for finger placement. Analogously, transcription of lncRNAs could serve as “grip holds” for nuclear proteins to pull the genome into new positions. This model could explain general lncRNA properties such as low abundance and tissue specificity. Overall, we propose a general framework for how the act of lncRNA transcription could play a role in organizing the 3D genome.
Keywords	cradle-to-cradle ; genome ; models ; non-coding RNA ; nuclear proteins ; packaging ; transcription (genetics)
Language	English
Dates of publication	2016-0602
Size	p. 657-664.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2016.05.011
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Single-cell profiling of lncRNA expression during Ebola virus infection in rhesus macaques

Luisa Santus / Maria Sopena-Rios / Raquel García-Pérez / Aaron E. Lin / Gordon C. Adams / Kayla G. Barnes / Katherine J. Siddle / Shirlee Wohl / Ferran Reverter / John L. Rinn / Richard S. Bennett / Lisa E. Hensley / Pardis C. Sabeti / Marta Melé

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 14

Abstract: Abstract Long non-coding RNAs (lncRNAs) are involved in numerous biological processes and are pivotal mediators of the immune response, yet little is known about their properties at the single-cell level. Here, we generate a multi-tissue bulk RNAseq ... ...

Abstract	Abstract Long non-coding RNAs (lncRNAs) are involved in numerous biological processes and are pivotal mediators of the immune response, yet little is known about their properties at the single-cell level. Here, we generate a multi-tissue bulk RNAseq dataset from Ebola virus (EBOV) infected and not-infected rhesus macaques and identified 3979 novel lncRNAs. To profile lncRNA expression dynamics in immune circulating single-cells during EBOV infection, we design a metric, Upsilon, to estimate cell-type specificity. Our analysis reveals that lncRNAs are expressed in fewer cells than protein-coding genes, but they are not expressed at lower levels nor are they more cell-type specific when expressed in the same number of cells. In addition, we observe that lncRNAs exhibit similar changes in expression patterns to those of protein-coding genes during EBOV infection, and are often co-expressed with known immune regulators. A few lncRNAs change expression specifically upon EBOV entry in the cell. This study sheds light on the differential features of lncRNAs and protein-coding genes and paves the way for future single-cell lncRNA studies.
Keywords	Science ; Q
Subject code	612
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cis and trans effects differentially contribute to the evolution of promoters and enhancers

Kaia Mattioli / Winona Oliveros / Chiara Gerhardinger / Daniel Andergassen / Philipp G. Maass / John L. Rinn / Marta Melé

Genome Biology, Vol 21, Iss 1, Pp 1-

2020 Volume 22

Abstract: Abstract Background Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects are caused by genetic variants located on the same DNA molecule as the target gene, trans effects are due to genetic variants ... ...

Abstract	Abstract Background Gene expression differences between species are driven by both cis and trans effects. Whereas cis effects are caused by genetic variants located on the same DNA molecule as the target gene, trans effects are due to genetic variants that affect diffusible elements. Previous studies have mostly assessed the impact of cis and trans effects at the gene level. However, how cis and trans effects differentially impact regulatory elements such as enhancers and promoters remains poorly understood. Here, we use massively parallel reporter assays to directly measure the transcriptional outputs of thousands of individual regulatory elements in embryonic stem cells and measure cis and trans effects between human and mouse. Results Our approach reveals that cis effects are widespread across transcribed regulatory elements, and the strongest cis effects are associated with the disruption of motifs recognized by strong transcriptional activators. Conversely, we find that trans effects are rare but stronger in enhancers than promoters and are associated with a subset of transcription factors that are differentially expressed between human and mouse. While we find that cis-trans compensation is common within promoters, we do not see evidence of widespread cis-trans compensation at enhancers. Cis-trans compensation is inversely correlated with enhancer redundancy, suggesting that such compensation may often occur across multiple enhancers. Conclusions Our results highlight differences in the mode of evolution between promoters and enhancers in complex mammalian genomes and indicate that studying the evolution of individual regulatory elements is pivotal to understand the tempo and mode of gene expression evolution.
Keywords	Regulatory element evolution ; Gene expression evolution ; Massively parallel reporter assays ; Cis and trans effects ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	572
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Sox2 transcription factor binds RNA

Zachariah E. Holmes / Desmond J. Hamilton / Taeyoung Hwang / Nicholas V. Parsonnet / John L. Rinn / Deborah S. Wuttke / Robert T. Batey

Nature Communications, Vol 11, Iss 1, Pp 1-

2020 Volume 12

Abstract: Some transcription factors have been proposed to functionally interact with RNA to facilitate proper regulation of gene expression. Here the authors demonstrate that human Sox2 interact directly and with high affinity to RNAs through its HMG DNA-binding ... ...

Abstract	Some transcription factors have been proposed to functionally interact with RNA to facilitate proper regulation of gene expression. Here the authors demonstrate that human Sox2 interact directly and with high affinity to RNAs through its HMG DNA-binding domain.
Keywords	Science ; Q
Language	English
Publishing date	2020-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enhancers in the Peril lincRNA locus regulate distant but not local genes

Abigail F. Groff / A. Rasim Barutcu / Jordan P. Lewandowski / John L. Rinn

Genome Biology, Vol 19, Iss 1, Pp 1-

2018 Volume 14

Abstract: Abstract Background Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies ... ...

Abstract	Abstract Background Recently, it has become clear that some promoters function as long-range regulators of gene expression. However, direct and quantitative assessment of enhancer activity at long intergenic noncoding RNA (lincRNA) or mRNA gene bodies has not been performed. To unbiasedly assess the enhancer capacity across lincRNA and mRNA loci, we performed a massively parallel reporter assay (MPRA) on six lincRNA loci and their closest protein-coding neighbors. Results For both gene classes, we find significantly more MPRA activity in promoter regions than in gene bodies. However, three lincRNA loci, Lincp21, LincEnc1, and Peril, and one mRNA locus, Morc2a, display significant enhancer activity within their gene bodies. We hypothesize that such peaks may mark long-range enhancers, and test this in vivo using RNA sequencing from a knockout mouse model and high-throughput chromosome conformation capture (Hi-C). We find that ablation of a high-activity MPRA peak in the Peril gene body leads to consistent dysregulation of Mccc1 and Exosc9 in the neighboring topologically associated domain (TAD). This occurs irrespective of Peril lincRNA expression, demonstrating this regulation is DNA-dependent. Hi-C confirms long-range contacts with the neighboring TAD, and these interactions are altered upon Peril knockout. Surprisingly, we do not observe consistent regulation of genes within the local TAD. Together, these data suggest a long-range enhancer-like function for the Peril gene body. Conclusions A multi-faceted approach combining high-throughput enhancer discovery with genetic models can connect enhancers to their gene targets and provides evidence of inter-TAD gene regulation.
Keywords	lincRNA ; Mouse models ; MPRA ; Cis-regulation ; Enhancer ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	612
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention

Gabrijela Dumbović / Ulrich Braunschweig / Heera K. Langner / Michael Smallegan / Josep Biayna / Evan P. Hass / Katarzyna Jastrzebska / Benjamin Blencowe / Thomas R. Cech / Marvin H. Caruthers / John L. Rinn

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 19

Abstract: RNA localization plays an important role in transcriptome regulation. The majority of TERT transcripts are detected in the nucleus and TUG1 lncRNAs in both the nucleus and cytoplasm. Here, the authors combine single-cell RNA imaging, antisense ... ...

Abstract	RNA localization plays an important role in transcriptome regulation. The majority of TERT transcripts are detected in the nucleus and TUG1 lncRNAs in both the nucleus and cytoplasm. Here, the authors combine single-cell RNA imaging, antisense oligonucleotides and splicing analyses to show that retention of specific introns drives stable compartmentalization of TERT and TUG1 transcripts in the nucleus, and that splicing of TERT retained introns is mitotically regulated.
Keywords	Science ; Q
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In vivo Firre and Dxz4 deletion elucidates roles for autosomal gene regulation

Daniel Andergassen / Zachary D Smith / Jordan P Lewandowski / Chiara Gerhardinger / Alexander Meissner / John L Rinn

eLife, Vol

2019 Volume 8

Abstract: Recent evidence has determined that the conserved X chromosome mega-structures controlled by the Firre and Dxz4 loci are not required for X chromosome inactivation (XCI) in cell lines. Here, we examined the in vivo contribution of these loci by ... ...

Abstract	Recent evidence has determined that the conserved X chromosome mega-structures controlled by the Firre and Dxz4 loci are not required for X chromosome inactivation (XCI) in cell lines. Here, we examined the in vivo contribution of these loci by generating mice carrying a single or double deletion of Firre and Dxz4. We found that these mutants are viable, fertile and show no defect in random or imprinted XCI. However, the lack of these elements results in many dysregulated genes on autosomes in an organ-specific manner. By comparing the dysregulated genes between the single and double deletion, we identified superloop, megadomain, and Firre locus-dependent gene sets. The largest transcriptional effect was observed in all strains lacking the Firre locus, indicating that this locus is the main driver for these autosomal expression signatures. Collectively, these findings suggest that these X-linked loci are involved in autosomal gene regulation rather than XCI biology.
Keywords	X chromosome inactivation ; FIRRE ; DXZ4 ; chromosome structure ; NHCC ; Intra-chromosomal organization ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genome-wide CRISPR interference screen identifies long non-coding RNA loci required for differentiation and pluripotency

Jeffrey R. Haswell / Kaia Mattioli / Chiara Gerhardinger / Philipp G. Maass / Daniel J. Foster / Paola Peinado / Xiaofeng Wang / Pedro P. Medina / John L. Rinn / Frank J. Slack

PLoS ONE, Vol 16, Iss

2021 Volume 11

Abstract: Although many long non-coding RNAs (lncRNAs) exhibit lineage-specific expression, the vast majority remain functionally uncharacterized in the context of development. Here, we report the first described human embryonic stem cell (hESC) lines to repress ( ... ...

Abstract	Although many long non-coding RNAs (lncRNAs) exhibit lineage-specific expression, the vast majority remain functionally uncharacterized in the context of development. Here, we report the first described human embryonic stem cell (hESC) lines to repress (CRISPRi) or activate (CRISPRa) transcription during differentiation into all three germ layers, facilitating the modulation of lncRNA expression during early development. We performed an unbiased, genome-wide CRISPRi screen targeting thousands of lncRNA loci expressed during endoderm differentiation. While dozens of lncRNA loci were required for proper differentiation, most differentially expressed lncRNAs were not, supporting the necessity for functional screening instead of relying solely on gene expression analyses. In parallel, we developed a clustering approach to infer mechanisms of action of lncRNA hits based on a variety of genomic features. We subsequently identified and validated FOXD3-AS1 as a functional lncRNA essential for pluripotency and differentiation. Taken together, the cell lines and methodology described herein can be adapted to discover and characterize novel regulators of differentiation into any lineage.
Keywords	Medicine ; R ; Science ; Q
Subject code	571 ; 572
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: T-REX17 is a transiently expressed non-coding RNA essential for human endoderm formation

eLife, Vol

2023 Volume 12

Abstract: Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains ...

Abstract	Long non-coding RNAs (lncRNAs) have emerged as fundamental regulators in various biological processes, including embryonic development and cellular differentiation. Despite much progress over the past decade, the genome-wide annotation of lncRNAs remains incomplete and many known non-coding loci are still poorly characterized. Here, we report the discovery of a previously unannotated lncRNA that is transcribed 230 kb upstream of the SOX17 gene and located within the same topologically associating domain. We termed it T-REX17 (Transcript Regulating Endoderm and activated by soX17) and show that it is induced following SOX17 activation but its expression is more tightly restricted to early definitive endoderm. Loss of T-REX17 affects crucial functions independent of SOX17 and leads to an aberrant endodermal transcriptome, signaling pathway deregulation and epithelial to mesenchymal transition defects. Consequently, cells lacking the lncRNA cannot further differentiate into more mature endodermal cell types. Taken together, our study identified and characterized T-REX17 as a transiently expressed and essential non-coding regulator in early human endoderm differentiation.
Keywords	lncRNAs ; endoderm ; SOX17 ; enhancer ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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