BANP opens chromatin and activates CpG-island-regulated genes

Grand, Ralph S.; Burger, Lukas; Gräwe, Cathrin; Michael, Alicia K.; Isbel, Luke; Heß, Daniel; Hoerner, Leslie; Iešmantavičius, Vytautas; Durdu, Sevi; Pregnolato, Marco; Krebs, Arnaud R; Smallwood, Sébastien A.; Thomä, Nicolas H.; Vermeulen, Michiel; Schübeler, Dirk

doi:10.1038/s41586-021-03689-8

Cited by 62 publications

(89 citation statements)

References 85 publications

(107 reference statements)

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“…So, we first searched for enriched motifs in banp rw337 mutants using a motif discovery software called Hypergeometric Optimization of Motif EnRichment (HOMER) with ATAC-seq data. Consistent with a previous report on human and mouse BANP (Grand et al, 2021), our analysis revealed that TCTCGCGAGA, is the most enriched motif in the closed chromatin region of banp rw337 mutants (Fig. 6A and Fig.…”

Section: Resultssupporting

confidence: 93%

Banp regulates DNA damage response and chromosome segregation during the cell cycle in zebrafish retina

Babu

Takeuchi

Masai

2021

Preprint

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Btg3-associated nuclear protein (Banp) was originally identified as a nuclear matrix-associated protein and it functions as a tumor suppressor. At molecular level, Banp regulates transcription of metabolic genes via a CGCG-containing motif called the Banp motif. However, its physiological roles in embryonic development are unknown. Here we report that Banp is indispensable for DNA damage response and chromosome segregation during mitosis. Zebrafish banp mutants show mitotic arrest and apoptosis in developing retina. We found that DNA replication stress and tp53-dependent DNA damage responses were activated to induce apoptosis in banp mutants, suggesting that Banp is required for integrity of DNA replication and DNA damage repair. Furthermore, in banp mutants, chromosome segregation was not smoothly processed from prometaphase to anaphase, leading to a prolonged M-phase. Our RNA- and ATAC-sequencing identified 31 candidates for direct Banp target genes that carry the Banp motif. Interestingly, two chromosome segregation regulators, cenpt and ncapg, are included in this list. Thus, Banp directly regulates transcription of cenpt and ncapg to promote chromosome segregation during mitosis. Our findings provide the first in vivo evidence that Banp is required for cell-cycle progression and cell survival by regulating DNA damage responses and chromosome segregation during mitosis.

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Section: Resultssupporting

confidence: 93%

Banp regulates DNA damage response and chromosome segregation during the cell cycle in zebrafish retina

Babu

Takeuchi

Masai

2021

Preprint

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“…However, some specificity in the enrichment was also observed. For example, although p53 and YY motifs were similarly enriched at promoters and enhancers, ETS (promoters vs. enhancers 9.5 versus 2.1 in linear scale) and recently discovered BANP 25 motifs (17.7 versus 2.0) were preferentially, and NRF1 (8.4 versus 1.3) as well as HNF1 motifs (4.3 versus 0.9) almost exclusively enriched at promoters (Fig. 5b,c ).…”

Section: Resultsmentioning

confidence: 84%

“…6d ). On the 5ʹ side, the strongest enrichment occurs close to the TSS, slowly decreasing toward the TATA box; preferential enrichment upstream of the TATA box was also observed for some TFs (e.g., BANP 25 ). On the 3ʹ side, the enrichment declines more sharply with very little motif enrichment observed beyond the +20 position from the TSS (Fig.…”

Section: Resultsmentioning

confidence: 92%

“…The motif collection and library design, measurement of enhancer activity of TF motif consensus sequences, and generation of activity PWM are described in detail in the Supplementary Methods . Moreover, previously described promoter motifs were used in TSS analyses, including TATA box, initiator, CCAAT-box and GC-box 58 ; BRE, MTE and DPE 59 ; and BANP 25 .…”

Section: Methodsmentioning

confidence: 99%

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Sequence determinants of human gene regulatory elements

et al. 2022

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DNA can determine where and when genes are expressed, but the full set of sequence determinants that control gene expression is unknown. Here, we measured the transcriptional activity of DNA sequences that represent an ~100 times larger sequence space than the human genome using massively parallel reporter assays (MPRAs). Machine learning models revealed that transcription factors (TFs) generally act in an additive manner with weak grammar and that most enhancers increase expression from a promoter by a mechanism that does not appear to involve specific TF–TF interactions. The enhancers themselves can be classified into three types: classical, closed chromatin and chromatin dependent. We also show that few TFs are strongly active in a cell, with most activities being similar between cell types. Individual TFs can have multiple gene regulatory activities, including chromatin opening and enhancing, promoting and determining transcription start site (TSS) activity, consistent with the view that the TF binding motif is the key atomic unit of gene expression.

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“…CpG islands (CGIs) are generally associated with housekeeping genes (1)(2)(3). BANP, a DNA methylationsensitive CGI binding protein, is required for their activation (4). CGIs are also associated with bivalent genes (5,6), and it is intriguing to ask whether and how CGI-associated bivalent genes are regulated by sequence-specific recognition.…”

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confidence: 99%

Highly enriched BEND3 prevents the premature activation of bivalent genes during differentiation

Zhang

Yan

You

et al. 2022

Science

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Bivalent genes are ready for activation upon the arrival of developmental cues. Here, we report that BEND3 is a CpG island (CGI)–binding protein that is enriched at regulatory elements. The cocrystal structure of BEND3 in complex with its target DNA reveals the structural basis for its DNA methylation–sensitive binding property. Mouse embryos ablated of Bend3 died at the pregastrulation stage. Bend3 null embryonic stem cells (ESCs) exhibited severe defects in differentiation, during which hundreds of CGI-containing bivalent genes were prematurely activated. BEND3 is required for the stable association of polycomb repressive complex 2 (PRC2) at bivalent genes that are highly occupied by BEND3, which suggests a reining function of BEND3 in maintaining high levels of H3K27me3 at these bivalent genes in ESCs to prevent their premature activation in the forthcoming developmental stage.

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BANP opens chromatin and activates CpG-island-regulated genes

Abstract: Genotype of cell lines was tested at the level of DNA sequence and protein (Western blotting). Mycoplasma contaminationCell lines tested negative for Mycoplasm.

Cited by 62 publications

References 85 publications

Banp regulates DNA damage response and chromosome segregation during the cell cycle in zebrafish retina

Banp regulates DNA damage response and chromosome segregation during the cell cycle in zebrafish retina

Sequence determinants of human gene regulatory elements

Highly enriched BEND3 prevents the premature activation of bivalent genes during differentiation

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