An atlas of silencer elements for the human and mouse genomes
Posted on: 4 April 2018 , updated on: 12 April 2018
Preprint posted on 23 January 2018
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-020-14853-5
Enhancers’ antimatter? Putative silencer elements mapped genome-wide in mouse and human
Selected by Rafael GalupaCategories: developmental biology, genomics
Background
It has long been recognised that DNA elements located sometimes hundreds of kilobases away from gene promoters can influence their expression in cis. The most commonly explored class of these cis-regulatory elements are enhancers, which by definition contribute to activating gene expression. However, some elements have the opposite effect – they negatively affect gene expression in cis, and have therefore been named “silencer” elements. Silencers are completely unexplored – we lack a systematic study of not only where they are in the genome but also of what they are.
Key findings
The authors produced two atlases of putative silencer elements that are cell-type specific, composed of ~1.5 million elements in the human genome, and ~1 million in mouse.
How were they identified? Assuming that silencers need to bind repressor factors and will therefore correspond to DNase hypersensitivity sites (DHS), the authors considered DHS from 82 human cell lines (ENCODE+Roadmap) or from 22 mouse cell lines (ENCODE) and then excluded all that overlapped with chromatin features of enhancers (H3K4me1), promoters (H3K4me3 and TSS) or insulator elements (CTCF binding). The remaining DHS were filtered for cell-type specificity and considered “putative silencer elements” – each cell type contains an average of tenths of thousand elements.
Characteristics of (putative) silencers
Features explored | Results |
Binding sites for repressor transcription factors (TFs) | Enriched for binding of REST, YY1, ZBTB33, SUZ12 and EZH2 (based on ChIP-seq) and also for motifs of other repressor TFs |
DNA methylation | Many silencers are hypermethylated (contrary to enhancers, which are normally un- or lowly methylated). On average, silencers are 75% methylated versus 43% for enhancers |
Chromatin signatures (Roadmap) | Most silencers fall into the uncharacterised category (not annotated/lack of signal). Otherwise the three next most enriched categories correspond to weak transcription, weak polycomb and heterochromatin |
Sequence conservation | No or very poor conservation across 100 vertebrates analysed (enhancers are poorly conserved as well) |
Promoter interactions (promoter capture Hi-C) | Majority of promoter interactions correspond to non-expressed or lowly expressed genes. Overall expression of all genes interacting with silencers is significantly lower than for genes interacting with enhancers. |
Disease traits (SNPs) | 25% of disease traits present are enriched at silencers, similar to other cis-regulatory elements |
Validation of silencer elements: The authors performed MPRA/STARR-seq (click here for a review on high-throughput approaches to test cis-regulatory elements) with 7430 putative silencers, 20 “known” silencers, 20 known enhancers and 20 random regions. Median expression levels of the reporter promoter cloned together with putative silencers was similar to that of random regions and close to 1 (i.e. no change in promoter activity); 51% of putative silencers did induce lower levels of expression compared to controls – these were considered true silencers and motifs found de novo on these were closest to REST and YY1 known motifs.
Interestingly, the authors also found that a subset of silencers can act as enhancers (or as part of enhancer elements) in other cell types: 25-65% silencers (in human; mouse: 1-55%) showed enhancer chromatin features in at least one other cell type. In the cell types in which silencers have enhancer features, the expression of promoters with which they interact is significantly higher than in the cell lines where silencers were identified.
What I like about this preprint
Most of us have heard about enhancer elements, but the idea that some cis-regulatory elements might actually work as repressors is less well-appreciated. During my PhD project, I have come across such elements while trying to find enhancers – they even displayed enhancer signatures but then had a negative effect on target genes (in cis). I’m still trying to understand how they might be working. So these atlases of putative silencers represent a valuable starting point to begin exploring the biology of these elements.
Open questions
Genetics is still in my view the golden standard to test and define cis-regulatory elements – it will thus be very important to genetically dissect these silencer elements at their endogenous loci and verify their role as cis-repressors of gene expression. Maybe the easiest approach would be to select an amenable cell type for genomic engineering and target the top ten strongest silencers (as identified with MPRA/STARR-seq) specific for that cell type.
Read preprintSign up to customise the site to your preferences and to receive alerts
Register hereAlso in the developmental biology category:
Actin-based deformations of the nucleus control multiciliated ependymal cell differentiation
Ryan Harrison
HIF1A contributes to the survival of aneuploid and mosaic pre-implantation embryos
Anchel De Jaime Soguero
Axis reset is rate limiting for onset of whole-body regenerative abilities during planarian development
Isabella Cisneros
Also in the genomics category:
A fine kinetic balance of interactions directs transcription factor hubs to genes
Deevitha Balasubramanian
Enhancer-driven cell type comparison reveals similarities between the mammalian and bird pallium
Rodrigo Senovilla-Ganzo
Modular control of time and space during vertebrate axis segmentation
AND
Natural genetic variation quantitatively regulates heart rate and dimension
Girish Kale, Jennifer Ann Black
preListsdevelopmental biology category:
in theBSDB/GenSoc Spring Meeting 2024
A list of preprints highlighted at the British Society for Developmental Biology and Genetics Society joint Spring meeting 2024 at Warwick, UK.
List by | Joyce Yu, Katherine Brown |
GfE/ DSDB meeting 2024
This preList highlights the preprints discussed at the 2024 joint German and Dutch developmental biology societies meeting that took place in March 2024 in Osnabrück, Germany.
List by | Joyce Yu |
‘In preprints’ from Development 2022-2023
A list of the preprints featured in Development's 'In preprints' articles between 2022-2023
List by | Alex Eve, Katherine Brown |
preLights peer support – preprints of interest
This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.
List by | preLights peer support |
The Society for Developmental Biology 82nd Annual Meeting
This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.
List by | Joyce Yu, Katherine Brown |
CSHL 87th Symposium: Stem Cells
Preprints mentioned by speakers at the #CSHLsymp23
List by | Alex Eve |
Journal of Cell Science meeting ‘Imaging Cell Dynamics’
This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.
List by | Helen Zenner |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Alumni picks – preLights 5th Birthday
This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.
List by | Sergio Menchero et al. |
CellBio 2022 – An ASCB/EMBO Meeting
This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.
List by | Nadja Hümpfer et al. |
2nd Conference of the Visegrád Group Society for Developmental Biology
Preprints from the 2nd Conference of the Visegrád Group Society for Developmental Biology (2-5 September, 2021, Szeged, Hungary)
List by | Nándor Lipták |
Fibroblasts
The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!
List by | Osvaldo Contreras |
EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)
A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.
List by | Alex Eve |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
List by | Jesus Victorino |
Single Cell Biology 2020
A list of preprints mentioned at the Wellcome Genome Campus Single Cell Biology 2020 meeting.
List by | Alex Eve |
Society for Developmental Biology 79th Annual Meeting
Preprints at SDB 2020
List by | Irepan Salvador-Martinez, Martin Estermann |
FENS 2020
A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020
List by | Ana Dorrego-Rivas |
Planar Cell Polarity – PCP
This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.
List by | Ana Dorrego-Rivas |
Cell Polarity
Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.
List by | Yamini Ravichandran |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |
3D Gastruloids
A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.
List by | Paul Gerald L. Sanchez and Stefano Vianello |
ASCB EMBO Annual Meeting 2019
A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)
List by | Madhuja Samaddar et al. |
EDBC Alicante 2019
Preprints presented at the European Developmental Biology Congress (EDBC) in Alicante, October 23-26 2019.
List by | Sergio Menchero et al. |
EMBL Seeing is Believing – Imaging the Molecular Processes of Life
Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019
List by | Dey Lab |
SDB 78th Annual Meeting 2019
A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.
List by | Alex Eve |
Lung Disease and Regeneration
This preprint list compiles highlights from the field of lung biology.
List by | Rob Hynds |
Young Embryologist Network Conference 2019
Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London
List by | Alex Eve |
Pattern formation during development
The aim of this preList is to integrate results about the mechanisms that govern patterning during development, from genes implicated in the processes to theoritical models of pattern formation in nature.
List by | Alexa Sadier |
BSCB/BSDB Annual Meeting 2019
Preprints presented at the BSCB/BSDB Annual Meeting 2019
List by | Dey Lab |
Zebrafish immunology
A compilation of cutting-edge research that uses the zebrafish as a model system to elucidate novel immunological mechanisms in health and disease.
List by | Shikha Nayar |
Also in the genomics category:
BSCB-Biochemical Society 2024 Cell Migration meeting
This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.
List by | Reinier Prosee |
9th International Symposium on the Biology of Vertebrate Sex Determination
This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.
List by | Martin Estermann |
Semmelweis Symposium 2022: 40th anniversary of international medical education at Semmelweis University
This preList contains preprints discussed during the 'Semmelweis Symposium 2022' (7-9 November), organised around the 40th anniversary of international medical education at Semmelweis University covering a wide range of topics.
List by | Nándor Lipták |
20th “Genetics Workshops in Hungary”, Szeged (25th, September)
In this annual conference, Hungarian geneticists, biochemists and biotechnologists presented their works. Link: http://group.szbk.u-szeged.hu/minikonf/archive/prg2021.pdf
List by | Nándor Lipták |
EMBL Conference: From functional genomics to systems biology
Preprints presented at the virtual EMBL conference "from functional genomics and systems biology", 16-19 November 2020
List by | Jesus Victorino |
TAGC 2020
Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20
List by | Maiko Kitaoka et al. |