Short tandem repeats recruit transcription factors to tune eukaryotic gene expression

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

doi:10.1016/j.bpj.2021.11.1305

Cited by 14 publications

(26 citation statements)

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“…This is consistent with the fact that enhancer sequences are largely species-specific, being conserved only between close phyla, in sharp contrast to genes (74, 187, 232). Simple repeats may also be involved (47, 108, 109). Any young TE is subjected to repression upon insertion and can seemingly behave as a ProB element.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, simple repeats are commonly transcribed and high GC skewing of CorrB non-TE RepSeq suggests that they are prone to forming R-loops upon transcription (44)(45)(46). Simple repeats are known to specifically bind a host of TFs (47). Both Z-DNA and R-loop forming potential has also been demonstrated for TEs, especially SINEs and ERVs (46,(48)(49)(50).…”

Section: Identifying Cis-determinants Of A/b Partitioning: Proa and P...mentioning

confidence: 99%

“…A growing body of literature shows that, in all tissues where this has been investigated, a significant proportion of DHS/enhancers active in a given cell type are in fact RepSeqs (26,(104)(105)(106)(107). Mounting evidence further suggests that all DHS/enhancers are of RepSeq origin, deriving either from TE or non-TE sequences, which may essentially have become undetectable due to sequence drift across evolutionary times (see Box1) (47,74,(108)(109)(110).…”

Section: Dhs/enhancers Are Of Repseq Originmentioning

confidence: 99%

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ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Bonnet,

Hulo,

Mourad

et al. 2023

Preprint

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SUMMARYThere is a growing awareness that repeat sequences (RepSeq) - the main constituents of the human genome - are also prime players in its organization. Here we propose that the genome should be envisioned as a supersystem with three main subsystems, each composed of functionally redundant, cooperating elements. We define herein ProA and ProB RepSeqs as sequences that promote either the A/euchromatin or the B/heterochromatin compartment. ProA and ProB RepSeqs shape A/B partitioning, such that the relative proportions of ProA and ProB RepSeqs determine the propensity of a chromosome segment to adopt either an A or a B configuration. In human, core ProA RepSeqs are essentially made of Alu elements, whereas core ProB RepSeqs consist of young L1 and some Endogenous Retroviruses (ERVs) as well as a panel of AT-rich microsatellites and pericentromeric and telomeric satellites. Additionally, RepSeqs with more indefinite character and, importantly, their derivatives known as “transcriptional enhancers”, can shift between ProA and ProB functions and thus act to open or close specific chromatin domains depending on the cellular context. In this framework, genes and their promoters appear as a special class of RepSeqs that, in their active, transcribed state, reinforce the openness of their surroundings. Molecular mechanisms involve cooperativity between ProB elements, presumably underpinned by the condensate-like properties of heterochromatin, which ProA elements oppose in several ways. We provide strong arguments that altered CpG methylation patterns in cancer including a marked loss in the B compartment, result primarily from a global imbalance in the process of CpG methylation and its erasure. Our results suggest that the resulting altered methylation and impaired function of ProB RepSeqs globally weaken the B compartment, rendering it more plastic, which in turn may confer fate plasticity to the cancer cell.

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Section: Discussionmentioning

confidence: 99%

Section: Identifying Cis-determinants Of A/b Partitioning: Proa and P...mentioning

confidence: 99%

Section: Dhs/enhancers Are Of Repseq Originmentioning

confidence: 99%

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ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Bonnet,

Hulo,

Mourad

et al. 2023

Preprint

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“…Indeed, the optimal spacing of the Tead double motif is not found more frequently than other spacings in the genome, e.g., a relative spacing of +2 bp is more frequent (Figure 4B). Moreover, BPNet has been shown to learn relative motif affinities 17,20,23,101 and thus might be adept at learning degenerate versions of a motif.…”

Section: Enhancer Activation Involves Dna Distance-dependent Tf Coope...mentioning

confidence: 99%

Interpretable deep learning reveals the sequence rules of Hippo signaling

Dalal,

McAnany,

Weilert

et al. 2024

Preprint

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SummaryThe response to signaling pathways is highly context-specific, and identifying the transcription factors and mechanisms that are responsible is very challenging. Using the Hippo pathway in mouse trophoblast stem cells as a model, we show here that this information is encoded incis-regulatory sequences and can be learned from high-resolution binding data of signaling transcription factors. Using interpretable deep learning, we show that the binding levels of TEAD4 and YAP1 are enhanced in a distance-dependent manner by cell type-specific transcription factors, including TFAP2C. We also discovered that strictly spacedTead doublemotifs are widespread highly active canonical response elements that mediate cooperativity by promoting labile TEAD4 protein-protein interactions on DNA. These syntax rules and mechanisms apply genome-wide and allow us to predict how small sequence changes alter the activity of enhancersin vivo. This illustrates the power of interpretable deep learning to decode canonical and cell type-specific sequence rules of signaling pathways.Graphical abstract

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“…A recent research reported that short tandem repeats (STRs) can bind with TFs to tune eukaryotic gene expression. They anticipated that low-affinity binding sites can increase binding and proposed the STRs function as "rheostats" to tune local TF concentration and binding responses (35).…”

Section: Introductionmentioning

confidence: 99%

DNA-protein interaction is dominated by short anchoring elements

Chen,

Xu,

et al. 2023

Preprint

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To understand the regulation of gene expression, it is essential to elucidate the binding mechanism of DNA binding domain (DBD) of transcription factors (TFs), and predict the location of transcription factor binding sites (TFBSs). For an exhaustive search of TFBSs, we have investigated four typical TFs with diverse origins, such as WRKY, PU.1, GLUCOCORTICOID RECEPTOR (GR), and MYC2 by using a newly developed method, KaScape. During KaScape experiments, we identified short sequences (3-4 bases) or “anchoring element” (AE) for the four TFs that dominated the bound population of DNA-DBD binding. We further developed the AEEscape (AE Energy landscape) algorithm to detect and confirm the AE and derived its binding energy landscape for all possible sequences. Our analysis of the energy landscape revealed an energetic funnel around the TFBS, which is related to the AE density gradient in the region surrounding the TFBS. Our results provide novel insights into the mechanism of TF binding to TFBSs.

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Short tandem repeats recruit transcription factors to tune eukaryotic gene expression

Cited by 14 publications

References 0 publications

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

ProA and ProB repeat sequences shape genome organization, and enhancers open domains

Interpretable deep learning reveals the sequence rules of Hippo signaling

DNA-protein interaction is dominated by short anchoring elements

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