Short tandem repeats bind transcription factors to tune eukaryotic gene expression

Horton, Connor A.; Alexandari, Amr M.; Hayes, Michael G. B.; Marklund, Emil; Schaepe, Julia M.; Aditham, Arjun K.; Shah, Nilay; Suzuki, Peter H.; Shrikumar, Avanti; Afek, Ariel; Greenleaf, William J.; Gordân, Raluca; Zeitlinger, Julia; Kundaje, Anshul; Fordyce, Polly M.

doi:10.1126/science.add1250

Cited by 52 publications

(22 citation statements)

References 187 publications

(230 reference statements)

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“…It has been reported that short tandem repeats (STRs) are enriched in gene promoters and variable repeat number is associated with the gene expression (Sawaya et al, 2013; Vinces, Legendre, Caldara, Hagihara, & Verstrepen, 2009). Furthermore, approximately 90% of transcription factors preferentially bind to STRs (Horton et al, 2023). Therefore, we also analyzed the presence of STRs in the updated draft genome using TRF v4.09 (Benson, 1999).…”

Section: Resultsmentioning

confidence: 99%

Assembly of continuous high-resolution draft genome sequence ofHemicentrotus pulcherrimususing long-read sequencing

Komoto,

Ikeo,

Yaguchi

et al. 2023

Preprint

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The update of the draft genome assembly of sea urchin,Hemicentrotus pulcherrimus, which is widely studied in East Asia as a model organism of early development, was performed using Oxford nanopore long-read sequencing. The updated assembly provided ∼600 Mb genome sequences divided into 2,163 contigs with N50 = 516 kb. BUSCO completeness score and transcriptome model mapping ratio (TMMR) of the present assembly were obtained as 96.5 % and 77.8 % respectively. These results were more continuous with higher resolution than those by the previous version ofH. pulcerrimusdraft genome, HpulGenome_v1, where the number of scaffolds = 16,251 with a total of ∼100 Mb gaps, N50 = 143 kb, BUSCO completeness score = 86.1 %, and TMMR = 40.61. The obtained genome contained 36,055 gene models that were consistent with those in other echinoderms. Additionally, two tandem repeat sequences of early histone gene locus containing 47 copies and 34 copies of all histone genes, and 185 of the homologous sequences of the interspecifically conserved region of theArsinsulator, ArsInsC, were obtained. These results provide further advance for genome-wide research of development, gene regulation, and intranuclear structural dynamics of multicellular organisms usingHemicentrotus pulcherrimus.

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Section: Resultsmentioning

confidence: 99%

Assembly of continuous high-resolution draft genome sequence ofHemicentrotus pulcherrimususing long-read sequencing

Komoto,

Ikeo,

Yaguchi

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…The high copy numbers of (AT)n repeat motif in exome captures could be partially explained by the sequencing of TATA boxes located close to transcription start sites. The mononucleotide repeat (A)n and many other short tandem repeats have been linked to cis -regulatory elements in gene expression regulation in eukaryotes (Horton et al, 2023; Pholtaisong et al, 2022), explaining their abundance in exome captures. However, the abundance of poly-G repeats is a common artifact in two-channel Illumina sequencing systems observed when the dark base G is called after the termination of synthesis.…”

Section: Discussionmentioning

confidence: 99%

Optimizing Exome Captures in Species with Large Genomes Using Species-specific Repetitive DNA Blocker

Kesälahti,

Kumpula,

Cervantes

et al. 2024

Preprint

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Large and highly repetitive genomes are common. However, research interests usually lie within the non-repetitive parts of the genome, as they are more likely functional, and can be used to answer questions related to adaptation, selection, and evolutionary history. Exome capture is a cost-effective method for providing sequencing data from protein-coding parts of the genes. C0t-1 DNA blockers consist of repetitive DNA and are used in exome captures to prevent the hybridization of repetitive DNA sequences to capture baits or bait-bound genomic DNA. Universal blockers target repetitive regions shared by many species, while species-specific c0t-1 DNA is prepared from the DNA of the studied species, thus perfectly matching the repetitive DNA contents of the species. So far the use of species-specific c0t-1 DNA has been limited to a few model species. Here, we evaluated the performance of blocker treatments in exome captures of Pinus sylvestris, a widely distributed conifer species with a large (> 20 Gbp) and highly repetitive genome. We compared treatment with a commercial universal blocker to treatments with species-specific c0t-1 (30,000 ng and 60,000 ng). Species-specific c0t-1 captured more unique exons than the initial set of targets, reduced sequencing of tandem repeats, and produced more target regions with high read coverage and narrower depth distribution than the universal blocker. Based on our results, we recommend optimizing exome captures by using at least 60,000 ng species-specific c0t-1 DNA. It is relatively easy and fast to prepare and can also be used with existing bait set designs.

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“…We introduce a sequence diversity metric, defined as the average k-nearest neighbor (KNN) distance between a sequence and its neighbors from the same group, to quantify how similar designed sequences are to each other. Human regulatory DNA exhibits elevated GC content [20] and an abundance of particular subsequences like of GATA motifs [21], CpG islands [21], and short repeats [22]. Evaluating sequence composition with our quantitative metrics could therefore provide insight into the novelty and "humanness" of computationally designed CREs.…”

Section: Sequence Composition Analysismentioning

confidence: 99%

Polygraph: A Software Framework for the Systematic Assessment of Synthetic Regulatory DNA Elements

Lal,

Gunsalus,

Gupta

et al. 2023

Preprint

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The design of regulatory elements is pivotal in numerous therapeutic interventions, including gene and cell therapy, wherein the typical objective is to engineer DNA sequences exhibiting specific attributes like cell-type specificity and elevated expression levels. However, the systematic assessment of these constructed DNA sequences remains challenging due to the absence of robust metrics and an integrated software framework. Here, we introduce Polygraph, a Python framework for evaluating synthetic DNA sequences. Polygraph provides a variety of features to streamline the synthesis and scrutiny of regulatory elements, incorporating features like a diversity index, motif and k-mer composition, similarity to endogenous regulatory sequences, and screening with predictive and foundational models. Consequently, Polygraph stands as the first instrument for the assessment of synthetic regulatory sequences, enabling expedited progress in therapeutic applications and improving our understanding of gene regulatory mechanisms.

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Short tandem repeats bind transcription factors to tune eukaryotic gene expression

Cited by 52 publications

References 187 publications

Assembly of continuous high-resolution draft genome sequence ofHemicentrotus pulcherrimususing long-read sequencing

Assembly of continuous high-resolution draft genome sequence ofHemicentrotus pulcherrimususing long-read sequencing

Optimizing Exome Captures in Species with Large Genomes Using Species-specific Repetitive DNA Blocker

Polygraph: A Software Framework for the Systematic Assessment of Synthetic Regulatory DNA Elements

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