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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: 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: 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 11, p e

2021 Volume 0252848

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: IL-1β is upregulated in the diabetic retina and retinal vessels

Yang Liu / Montserrat Biarnés Costa / Chiara Gerhardinger

PLoS ONE, Vol 7, Iss 5, p e

cell-specific effect of high glucose and IL-1β autostimulation.

2012 Volume 36949

Abstract: Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1β-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1β is well known for its role in the induction and, through autostimulation, ... ...

Abstract	Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1β-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1β is well known for its role in the induction and, through autostimulation, amplification of neuroinflammation. Upregulation of IL-1β has been consistently detected in the diabetic retina; however, the mechanisms and cellular source of IL-1β overexpression are poorly understood. The aim of this study was to investigate the effect of high glucose and IL-1β itself on IL-1β expression in microglial, macroglial (astrocytes and Müller cells) and retinal vascular endothelial cells; and to study the effect of diabetes on the expression of IL-1β in isolated retinal vessels and on the temporal pattern of IL-1β upregulation and glial reactivity in the retina of streptozotocin-diabetic rats. IL-1β was quantified by RealTime RT-PCR and ELISA, glial fibrillar acidic protein, α2-macroglobulin, and ceruloplasmin by immunoblotting. We found that high glucose induced a 3-fold increase of IL-1β expression in retinal endothelial cells but not in macroglia and microglia. IL-1β induced its own synthesis in endothelial and macroglial cells but not in microglia. In retinal endothelial cells, the high glucose-induced IL-1β overexpression was prevented by calphostin C, a protein kinase C inhibitor. The retinal vessels of diabetic rats showed increased IL-1β expression as compared to non-diabetic rats. Retinal expression of IL-1β increased early after the induction of diabetes, continued to increase with progression of the disease, and was temporally associated with upregulation of markers of glial activation. These findings point to hyperglycemia as the trigger and to the endothelium as the origin of the initial retinal upregulation of IL-1β in diabetes; and to IL-1β itself, via autostimulation in endothelial and macroglial cells, as the mechanism of sustained IL-1β overexpression. Interrupting the vicious circle triggered by IL-1β autostimulation could limit the ...
Keywords	Medicine ; R ; Science ; Q
Subject code	570 ; 571
Language	English
Publishing date	2012-01-01T00:00:00Z
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: Resolving mechanisms of immune‐mediated disease in primary CD4 T cells

Christophe Bourges / Abigail F Groff / Oliver S Burren / Chiara Gerhardinger / Kaia Mattioli / Anna Hutchinson / Theodore Hu / Tanmay Anand / Madeline W Epping / Chris Wallace / Kenneth GC Smith / John L Rinn / James C Lee

EMBO Molecular Medicine, Vol 12, Iss 5, Pp n/a-n/a (2020)

2020

Abstract: Abstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be ... ...

Abstract	Abstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune‐mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune‐mediated diseases but cannot be fine‐mapped. By studying the lead expression‐modulating SNP, we uncovered an NF‐κB‐driven regulatory circuit which constrains T‐cell activation through the dynamic formation of a super‐enhancer that upregulates TNFAIP3 (A20), a key NF‐κB inhibitor. In activated T cells, this feedback circuit is disrupted—and super‐enhancer formation prevented—by the risk variant at the lead SNP, leading to unrestrained T‐cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.
Keywords	CD4 T cells ; GWAS ; MPRA ; super‐enhancer ; TNFAIP3 ; Medicine (General) ; R5-920 ; Genetics ; QH426-470
Subject code	570
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

Jordan P. Lewandowski / James C. Lee / Taeyoung Hwang / Hongjae Sunwoo / Jill M. Goldstein / Abigail F. Groff / Nydia P. Chang / William Mallard / Adam Williams / Jorge Henao-Meija / Richard A. Flavell / Jeannie T. Lee / Chiara Gerhardinger / Amy J. Wagers / John L. Rinn

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 13

Abstract: LncRNA loci potentially contain multiple modes that can exert function, including DNA regulatory elements. Here, the authors generated genetic models in mice to dissect the role of the syntenically conserved lncRNA Firre in the context of hematopoiesis. ...

Abstract	LncRNA loci potentially contain multiple modes that can exert function, including DNA regulatory elements. Here, the authors generated genetic models in mice to dissect the role of the syntenically conserved lncRNA Firre in the context of hematopoiesis.
Keywords	Science ; Q
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Firre locus produces a trans-acting RNA molecule that functions in hematopoiesis

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 13

Abstract	LncRNA loci potentially contain multiple modes that can exert function, including DNA regulatory elements. Here, the authors generated genetic models in mice to dissect the role of the syntenically conserved lncRNA Firre in the context of hematopoiesis.
Keywords	Science ; Q
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Tug1 lncRNA locus is essential for male fertility

Jordan P. Lewandowski / Gabrijela Dumbović / Audrey R. Watson / Taeyoung Hwang / Emily Jacobs-Palmer / Nydia Chang / Christian Much / Kyle M. Turner / Christopher Kirby / Nimrod D. Rubinstein / Abigail F. Groff / Steve C. Liapis / Chiara Gerhardinger / Assaf Bester / Pier Paolo Pandolfi / John G. Clohessy / Hopi E. Hoekstra / Martin Sauvageau / John L. Rinn

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

2020 Volume 35

Abstract: Abstract Background Several long noncoding RNAs (lncRNAs) have been shown to function as components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, studying ... ...

Abstract	Abstract Background Several long noncoding RNAs (lncRNAs) have been shown to function as components of molecular machines that play fundamental roles in biology. While the number of annotated lncRNAs in mammalian genomes has greatly expanded, studying lncRNA function has been a challenge due to their diverse biological roles and because lncRNA loci can contain multiple molecular modes that may exert function. Results We previously generated and characterized a cohort of 20 lncRNA loci knockout mice. Here, we extend this initial study and provide a more detailed analysis of the highly conserved lncRNA locus, taurine-upregulated gene 1 (Tug1). We report that Tug1-knockout male mice are sterile with underlying defects including a low number of sperm and abnormal sperm morphology. Because lncRNA loci can contain multiple modes of action, we wanted to determine which, if any, potential elements contained in the Tug1 genomic region have any activity. Using engineered mouse models and cell-based assays, we provide evidence that the Tug1 locus harbors two distinct noncoding regulatory activities, as a cis-DNA repressor that regulates neighboring genes and as a lncRNA that can regulate genes by a trans-based function. We also show that Tug1 contains an evolutionary conserved open reading frame that when overexpressed produces a stable protein which impacts mitochondrial membrane potential, suggesting a potential third coding function. Conclusions Our results reveal an essential role for the Tug1 locus in male fertility and uncover evidence for distinct molecular modes in the Tug1 locus, thus highlighting the complexity present at lncRNA loci.
Keywords	Tug1 ; lncRNA ; Fertility ; DNA repressor ; Cis-regulatory elements ; RNA-seq ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	572
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In Vivo Characterization of Linc-p21 Reveals Functional cis-Regulatory DNA Elements

Abigail F. Groff / Diana B. Sanchez-Gomez / Marcela M.L. Soruco / Chiara Gerhardinger / A. Rasim Barutcu / Eric Li / Lara Elcavage / Olivia Plana / Lluvia V. Sanchez / James C. Lee / Martin Sauvageau / John L. Rinn

Cell Reports, Vol 16, Iss 8, Pp 2178-

2016 Volume 2186

Abstract: The Linc-p21 locus, encoding a long non-coding RNA, plays an important role in p53 signaling, cell-cycle regulation, and tumor suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the ... ...

Abstract	The Linc-p21 locus, encoding a long non-coding RNA, plays an important role in p53 signaling, cell-cycle regulation, and tumor suppression. However, despite extensive study, confusion exists regarding its mechanism of action: is activity driven by the transcript acting in trans, in cis, or by an underlying functional enhancer? Here, using a knockout mouse model and a massively parallel enhancer assay, we delineate the functional elements at this locus. We observe that, even in tissues with no detectable Linc-p21 transcript, deletion of the locus significantly affects local gene expression, including of the cell-cycle regulator Cdkn1a. To characterize this RNA-independent regulatory effect, we systematically interrogated the underlying DNA sequence for enhancer activity at nucleotide resolution and confirmed the existence of multiple enhancer elements. Together, these data suggest that, in vivo, the cis-regulatory effects mediated by Linc-p21, in the presence or absence of transcription, are due to DNA enhancer elements.
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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