Harnessing genetic variation at regulatory regions to fine-tune traits for climate resilient crops

Background: Mutations in more than 100 genes lead to dilated, hypertrophic and other forms of cardiomyopathy. Autosomal dominant mutations in the MYH7 and LMNA genes cause autosomal dominant hypertrophic and dilated cardiomyopathy, respectively. Individual mutations display a range of clinical expression from severe early onset disease to minimal or no symptoms. Genetic variation in noncoding gene regulatory regions including enhancers is expected to modify expression of cardiomyopathy genes and disease expressivity. In addition, heart failure is associated a fetal gene re-expression program, mediated by genetic regulatory regions. The contribution of noncoding genetic variation to cardiomyopathy and heart failure has been hampered by limited genome wide descriptions of human cardiac regulatory regions. Methods and Results: We used C ap A nalysis of G ene E xpression by sequencing (CAGE-seq) to profile the transcriptional start sites in healthy and failed human hearts. CAGE-seq detects the unidirectional signals of gene promoters and the bidirectional signal of transcribed enhancer regions. We identified ~17,000 transcriptional start sites associated with gene promoters and ~1,500 putative enhancer regions active in cardiac tissue. These CAGE-defined regulatory regions carried histone modifications and transcription factor binding properties characteristic of enhancers or promoters. We specifically identified promoter switching and differential enhancer usage between healthy and failed hearts. We intersected CAGE-defined enhancers with additional epigenomic datasets to identify regulatory regions for MYH7 and LMNA genes. We identified 13 putative enhancer regions and validated the functionality of a subset of these regulatory regions using reporter assays and gene editing. Conclusions: This CAGE-seq dataset defines the regulatory environment for heart failure. These promoter and enhancer regions could be used to target heart-failure associated gene expression changes. Additionally, this data can be used to identify enhancer regions regulating cardiomyopathy genes.

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Selection against archaic hominin genetic variation in regulatory regions

Nature Ecology & Evolution ◽

10.1038/s41559-020-01284-0 ◽

2020 ◽

Vol 4 (11) ◽

pp. 1558-1566 ◽

Cited By ~ 2

Author(s):

Natalie Telis ◽

Robin Aguilar ◽

Kelley Harris

Keyword(s):

Genetic Variation ◽

Regulatory Regions

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Different regulatory regions are located on the sensor domain of CpxA to fine-tune signal transduction

Research in Microbiology ◽

10.1016/j.resmic.2011.02.008 ◽

2011 ◽

Vol 162 (4) ◽

pp. 405-409 ◽

Cited By ~ 3

Author(s):

Rebecca Keller ◽

Judith Havemann ◽

Sabine Hunke

Keyword(s):

Signal Transduction ◽

Regulatory Regions ◽

Fine Tune

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Global reference mapping and dynamics of human transcription factor footprints

10.1101/2020.01.31.927798 ◽

2020 ◽

Cited By ~ 6

Author(s):

Jeff Vierstra ◽

John Lazar ◽

Richard Sandstrom ◽

Jessica Halow ◽

Kristen Lee ◽

...

Keyword(s):

Transcription Factor ◽

Genetic Variation ◽

Dnase I ◽

Regulatory Function ◽

Phenotypic Traits ◽

Regulatory Regions ◽

Functional Variants ◽

Nucleotide Resolution ◽

Regulatory Dna ◽

Transcription Factor Occupancy

AbstractCombinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits1, yet it remains challenging to distinguish variants that impact regulatory function2. Genomic DNase I footprinting enables quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin3–5. However, to date only a small fraction of such sites have been precisely resolved on the human genome sequence5. To enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate at nucleotide resolution ~4.5 million compact genomic elements encoding transcription factor occupancy. We map the fine-scale structure of ~1.6 million DHS and show that the overwhelming majority is populated by well-spaced sites of single transcription factor:DNA interaction. Cell context-dependent cis-regulation is chiefly executed by wholesale actuation of accessibility at regulatory DNA versus by differential transcription factor occupancy within accessible elements. We show further that the well-described enrichment of disease- and phenotypic trait-associated genetic variants in regulatory regions1,6 is almost entirely attributable to variants localizing within footprints, and that functional variants impacting transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find that the global density of human genetic variation is markedly increased within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a new framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation.

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Identification of genetic variation and putative regulatory regions in bovine CARD15

Mammalian Genome ◽

10.1007/s00335-005-0148-2 ◽

2006 ◽

Vol 17 (8) ◽

pp. 892-901 ◽

Cited By ~ 21

Author(s):

Kristen H. Taylor ◽

Jeremy F. Taylor ◽

Stephen N. White ◽

James E. Womack

Keyword(s):

Genetic Variation ◽

Regulatory Regions

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Novel players fine-tune plant trade-offs

Essays in Biochemistry ◽

10.1042/bse0580083 ◽

2015 ◽

Vol 58 ◽

pp. 83-100 ◽

Cited By ~ 25

Author(s):

Selena Gimenez-Ibanez ◽

Marta Boter ◽

Roberto Solano

Keyword(s):

Ubiquitin Ligase ◽

Feedback Loop ◽

Molecular Level ◽

26S Proteasome ◽

Signalling Molecules ◽

Transcriptional Reprogramming ◽

Trade Offs ◽

Jaz Proteins ◽

Regulatory Feedback Loop ◽

Fine Tune

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.

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