Skip to main content
SpringerLink
Log in

From sequence to consequence: Deciphering the complex cis-regulatory landscape

  • Review
  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Cell type-specific expression of genes plays a pivotal role in the development and evolution of multicellular organisms over millions of years. The majority of regulatory control resides within the non-coding regions of the genome, referred to as ‘dark matter’, which contains cis-regulatory modules. These cis-regulatory modules function collectively and can impact gene expression even when located far from the target gene, exhibiting context-specific behaviour. Consequently, the cis-regulatory code governing gene expression patterns is intricate, in contrast to the universally understood genetic code. This overview centres on the current knowledge regarding cis-regulatory elements, primarily enhancers and their role in governing the spatiotemporal gene expression patterns, and how they have evolved and adapted across different species.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

References

  • Abatti LE, Lado-Fernandez P, Huynh L, et al. 2023 Epigenetic reprogramming of a distal developmental enhancer cluster drives SOX2 overexpression in breast and lung adenocarcinoma. Nucleic Acids Res. 51 10109–10131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akgol Oksuz B, Yang L, Abraham S, et al. 2021 Systematic evaluation of chromosome conformation capture assays. Nat. Methods 18 1046–1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akiyama N, Sato S, Tanaka KM, et al. 2022 The role of the epidermis enhancer element in positive and negative transcriptional regulation of ebony in Drosophila melanogaster. G3 (Bethesda) 12

  • Andrews G, Fan K, Pratt HE, et al. 2023 Mammalian evolution of human cis-regulatory elements and transcription factor binding sites. Science 380 eabn7930

    Article  CAS  PubMed  Google Scholar 

  • Arnold CD, Gerlach D, Stelzer C, et al. 2013 Genome-wide quantitative enhancer activity maps identified by STARR-seq. Science 339 1074–1077

    Article  ADS  CAS  PubMed  Google Scholar 

  • Barr KA, Martinez C, Moran JR, et al. 2017 Synthetic enhancer design by in silico compensatory evolution reveals flexibility and constraint in cis-regulation. BMC Syst. Biol. 11 116

    Article  PubMed  PubMed Central  Google Scholar 

  • Blayney JW, Francis H, Rampasekova A, et al. 2023 Super-enhancers include classical enhancers and facilitators to fully activate gene expression. Cell 186 5826–5839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buenrostro JD, Wu B, Chang HY, et al. 2015 ATAC-seq: A method for assaying chromatin accessibility genome-wide. Curr. Protoc. Mol. Biol. 109 1–9

    Article  Google Scholar 

  • Chen Y, Ying Y, Wang M, et al. 2023 A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer. Cell Death Dis. 14 8

    Article  PubMed  PubMed Central  Google Scholar 

  • Cherry TJ, Yang MG, Harmin DA, et al. 2020 Mapping the cis-regulatory architecture of the human retina reveals noncoding genetic variation in disease. Proc. Natl. Acad. Sci. USA 117 9001–9012

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Clement Y, Torbey P, Gilardi-Hebenstreit P, et al. 2020 Enhancer-gene maps in the human and zebrafish genomes using evolutionary linkage conservation. Nucleic Acids Res. 48 2357–2371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Enard W, Khaitovich P, Klose J, et al. 2002 Intra- and interspecific variation in primate gene expression patterns. Science 296 340–343

    Article  ADS  CAS  PubMed  Google Scholar 

  • Espinola SM, Götz M, Bellec M, et al. 2021 Cis-regulatory chromatin loops arise before TADs and gene activation, and are independent of cell fate during early Drosophila development. Nat. Genet. 53 477–486

    Article  CAS  PubMed  Google Scholar 

  • Friedman RZ, Granas DM, Myers CA, et al. 2021 Information content differentiates enhancers from silencers in mouse photoreceptors. eLife 10 e67403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Galupa R, Alvarez-Canales G, Borst NO, et al. 2023 Enhancer architecture and chromatin accessibility constrain phenotypic space during Drosophila development. Dev. Cell 58 51–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ginley-Hidinger M, Abewe H, Osborne K, et al. 2023 Cis-regulatory control of transcriptional timing and noise in response to estrogen. bioRxiv. https://doi.org/10.1101/2023.03.14.532457

    Article  Google Scholar 

  • Grosveld F, van Staalduinen J and Stadhouders R 2021 Transcriptional regulation by (super)enhancers: from discovery to mechanisms. Annu. Rev. Genomics. Hum. Genet. 22 127–146

    Article  PubMed  Google Scholar 

  • Ho Y, Liebhaber SA and Cooke NE 2004 Activation of the human GH gene cluster: roles for targeted chromatin modification. Trends Endocrinol. Metab. 15 40–45

    Article  CAS  PubMed  Google Scholar 

  • Johnson DS, Mortazavi A, Myers RM, et al. 2007 Genome-wide mapping of in vivo protein–DNA interactions. Science 316 1497–1502

    Article  ADS  CAS  PubMed  Google Scholar 

  • Junion G, Spivakov M, Girardot C, et al. 2012 A transcription factor collective defines cardiac cell fate and reflects lineage history. Cell 148 473–486

    Article  CAS  PubMed  Google Scholar 

  • Kashima Y, Sakamoto Y, Kaneko K, et al. 2020 Single-cell sequencing techniques from individual to multiomics analyses. Exp. Mol. Med. 52 1419–1427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim S and Wysocka J 2023 Deciphering the multi-scale, quantitative cis-regulatory code. Mol. Cell. 83 373–392

    Article  CAS  PubMed  Google Scholar 

  • King DM, Hong CKY, Shepherdson JL, et al. 2020 Synthetic and genomic regulatory elements reveal aspects of cis-regulatory grammar in mouse embryonic stem cells. eLife 9 e41279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kulkarni MM and Arnosti DN 2003 Information display by transcriptional enhancers. Development 130 6569–6575

    Article  CAS  PubMed  Google Scholar 

  • Le Poul Y, Xin Y, Ling L, et al. 2020 Regulatory encoding of quantitative variation in spatial activity of a Drosophila enhancer. Sci. Adv. 6 eabe2955

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  • Li K, Liu Y, Cao H, et al. 2020 Interrogation of enhancer function by enhancer-targeting CRISPR epigenetic editing. Nat. Commun. 11 485

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  • Li Q, Peterson KR, Fang X, et al. 2002 Locus control regions. Blood 100 3077–3086

    Article  CAS  PubMed  Google Scholar 

  • Li W, Notani D, Ma Q, et al. 2013 Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature 498 516–520

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Li W, Lu J, Lu P, et al. 2023 scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells. Nat. Methods 20 1493–1505

    Article  CAS  PubMed  Google Scholar 

  • Lim CKW, McCallister TX, Saporito-Magriña C, et al. 2022 CRISPR base editing of cis-regulatory elements enables the perturbation of neurodegeneration-linked genes. Mol. Ther. 30 3619–3631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin X, Liu Y, Liu S, et al. 2022 Nested epistasis enhancer networks for robust genome regulation. Science 377 1077–1085

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Machacova S, Kozmik Z and Kozmikova I 2022 Identification of Nodal-dependent enhancer of amphioxus Chordin sufficient to drive gene expression into the chordate dorsal organizer. Dev. Genes Evol. 232 137–145

    Article  CAS  PubMed  Google Scholar 

  • Majic P and Payne JL 2020 Enhancers facilitate the birth of de novo genes and gene integration into regulatory networks. Mol. Biol. Evol. 37 1165–1178

    Article  CAS  PubMed  Google Scholar 

  • Mukund AX, Tycko J, Allen SJ, et al. 2023 High-throughput functional characterization of combinations of transcriptional activators and repressors. Cell Syst. 14 746–763

    Article  CAS  PubMed  Google Scholar 

  • Nair RR, Blankvoort S, Lagartos MJ, et al. 2020 Enhancer-driven gene expression (EDGE) enables the generation of viral vectors specific to neuronal subtypes. iScience 23 100888

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Oksuz O, Henninger JE, Warneford-Thomson R, et al. 2023 Transcription factors interact with RNA to regulate genes. Mol. Cell. 83 2449–2463

    Article  CAS  PubMed  Google Scholar 

  • Osterwalder M, Barozzi I, Tissières V, et al. 2018 Enhancer redundancy provides phenotypic robustness in mammalian development. Nature 554 239–243

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Panne D, Maniatis T and Harrison SC 2007 An atomic model of the interferon-beta enhanceosome. Cell 129 1111–1123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potier D, Seyres D, Guichard C, et al. 2014 Identification of cis-regulatory modules encoding temporal dynamics during development. BMC Genom. 15 534

    Article  Google Scholar 

  • Ramalingam V, Yu X, Slaughter BD, et al. 2023 Lola-I is a promoter pioneer factor that establishes de novo Pol II pausing during development. Nat. Commun. 14 5862

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramani V, Deng X, Qiu R, et al. 2020 Sci-Hi-C: A single-cell Hi-C method for mapping 3D genome organization in large number of single cells. Methods 170 61–68

    Article  CAS  PubMed  Google Scholar 

  • Rastegar S, Hess I, Dickmeis T, et al. 2008 The words of the regulatory code are arranged in a variable manner in highly conserved enhancers. Dev. Biol. 318 366–377

    Article  CAS  PubMed  Google Scholar 

  • Sagai T, Amano T, Tamura M, et al. 2009 A cluster of three long-range enhancers directs regional Shh expression in the epithelial linings. Development 136 1665–1674

    Article  CAS  PubMed  Google Scholar 

  • Schaukowitch K, Joo JY, Liu X, et al. 2014 Enhancer RNA facilitates NELF release from immediate early genes. Mol. Cell 56 29–42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sigova AA, Abraham BJ, Ji X, et al. 2015 Transcription factor trapping by RNA in gene regulatory elements. Science 350 978–981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith GD, Ching WH, Cornejo-Páramo P, et al. 2023 Decoding enhancer complexity with machine learning and high-throughput discovery. Genome Biol. 24 116

    Article  PubMed  PubMed Central  Google Scholar 

  • Song L and Crawford GE 2010 DNase-seq: a high-resolution technique for mapping active gene regulatory elements across the genome from mammalian cells. Cold Spring Harb. Protoc. prot5384

  • Song M, Yang X, Ren X, et al. 2019 Mapping cis-regulatory chromatin contacts in neural cells links neuropsychiatric disorder risk variants to target genes. Nat. Genet. 51 1252–1262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taskiran II, Spanier KI, Christiaens V, et al. 2024 Cell type directed design of synthetic enhancers. Nature 626 212–220

  • Thanos D and Maniatis T 1995 Virus induction of human IFN beta gene expression requires the assembly of an enhanceosome. Cell 83 1091–1100

    Article  CAS  PubMed  Google Scholar 

  • Voichek Y, Hristova G, Mollá-Morales A, et al. 2023 Widespread transcriptional regulation from within transcribed regions in plants. bioRxiv. https://doi.org/10.1101/2023.09.15.557872v1

    Article  Google Scholar 

  • Wang W, Hu C-K, Zeng A, et al. 2020 Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates. Science 369 eaaz3090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Cairns MJ and Yan J 2019 Super-enhancers in transcriptional regulation and genome organization. Nucleic Acids Res. 47 11481–11496

    CAS  PubMed  PubMed Central  Google Scholar 

  • White MA 2015 Understanding how cis-regulatory function is encoded in DNA sequence using massively parallel reporter assays and designed sequences. Genomics 106 165–170

    Article  CAS  PubMed  Google Scholar 

  • Whyte WA, Orlando DA, Hnisz D, et al. 2013 Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153 307–319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong ES, Zheng D, Tan SZ, et al. 2020 Deep conservation of the enhancer regulatory code in animals. Science 370 eaax8137

    Article  CAS  PubMed  Google Scholar 

  • Xin Y, Le Poul Y, Ling L, et al. 2020 Enhancer evolutionary co-option through shared chromatin accessibility input. Proc. Natl. Acad. Sci. USA 117 20636–20644

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Yasmeen E, Wang J, Riaz M, et al. 2023 Designing artificial synthetic promoters for accurate, smart, and versatile gene expression in plants. Plant Commun. 4 100558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J and Zhou Q 2019 On the regulatory evolution of new genes throughout their life history. Mol. Biol. Evol. 36 15–27

    Article  PubMed  Google Scholar 

  • Zhou Z, Zhong Y, Zhang Z, et al. 2023 Spatial transcriptomics deconvolution at single-cell resolution using Redeconve. Nat. Commun. 14 7930

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Ankita Sharma for discussion and help with figures. Sincere apologies are rendered to any group whose studies have been missed out in the scope of this review. All figures were created using BioRender.com.

Funding

SG is supported by a JC Bose Fellowship from the Science and Engineering Research Board, Government of India (JCB/2019/000013). GJD is supported by a Senior Research Fellowship from the Indian Institute of Science Education and Research (IISER) Pune, India.

Author information

Authors and Affiliations

  1. Laboratory of Chromatin Biology and Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, 411 008, India

    Greg Jude Dsilva & Sanjeev Galande

  2. Centre of Excellence in Epigenetics, Department of Life Sciences, Shiv Nadar Institution of Eminence, Gautam Buddha Nagar, 201 324, India

    Sanjeev Galande

Authors
  1. Greg Jude Dsilva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sanjeev Galande
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GJD and SG contributed to the review article's conceptual framework, collected and analysed the literature, and wrote the manuscript. GJD prepared the figures.

Corresponding author

Correspondence to Sanjeev Galande.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Corresponding editor: Kundan Sengupta

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dsilva, G.J., Galande, S. From sequence to consequence: Deciphering the complex cis-regulatory landscape. J Biosci 49, 46 (2024). https://doi.org/10.1007/s12038-024-00431-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12038-024-00431-0

Keywords

Search

Navigation