DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium

Yizhar-Barnea, Ofer; Valensisi, Cristina; Jayavelu, Naresh Doni; Kishore, Kamal; Andrus, Colin; Koffler-Brill, Tal; Ushakov, Kathy; Perl, Kobi; Noy, Yael; Bhonker, Yoni; Pelizzola, Mattia; Hawkins, R. David; Avraham, Karen B.

doi:10.1038/s41598-018-35587-x

Cited by 28 publications

(29 citation statements)

References 78 publications

(96 reference statements)

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“…2c as the cumulative fold difference in accessibility of all peaks nearest to each gene. We further confirmed the efficacy and specificity of ATAC-seq by comparing the Sox2-EGFP high+ peaks with previously reported unmethylated regions and low methylated regions of the E16.5 cochlear sensory epithelium 65 (Supplementary Fig. 5).…”

Section: Resultssupporting

confidence: 85%

Open chromatin dynamics in prosensory cells of the embryonic mouse cochlea

Wilkerson

Chitsazan

VandenBosch

et al. 2019

Sci Rep

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Hearing loss is often due to the absence or the degeneration of hair cells in the cochlea. Understanding the mechanisms regulating the generation of hair cells may therefore lead to better treatments for hearing disorders. To elucidate the transcriptional control mechanisms specifying the progenitor cells (i.e. prosensory cells) that generate the hair cells and support cells critical for hearing function, we compared chromatin accessibility using ATAC-seq in sorted prosensory cells (Sox2-EGFP + ) and surrounding cells (Sox2-EGFP − ) from E12, E14.5 and E16 cochlear ducts. In Sox2-EGFP + , we find greater accessibility in and near genes restricted in expression to the prosensory region of the cochlear duct including Sox2 , Isl1 , Eya1 and Pou4f3 . Furthermore, we find significant enrichment for the consensus binding sites of Sox2, Six1 and Gata3—transcription factors required for prosensory development—in the open chromatin regions. Over 2,200 regions displayed differential accessibility with developmental time in Sox2-EGFP + cells, with most changes in the E12-14.5 window. Open chromatin regions detected in Sox2-EGFP + cells map to over 48,000 orthologous regions in the human genome that include regions in genes linked to deafness. Our results reveal a dynamic landscape of open chromatin in prosensory cells with potential implications for cochlear development and disease.

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Section: Resultssupporting

confidence: 85%

Open chromatin dynamics in prosensory cells of the embryonic mouse cochlea

Wilkerson

Chitsazan

VandenBosch

et al. 2019

Sci Rep

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“…1d). Xloc_012867 was first identified in our RNA-seq data of mouse inner ear [19] and was also described in our study on the mouse inner ear methylome [21].…”

Section: Computational Analysis Of Lncrnassupporting

confidence: 57%

“…The lncRNAs Gas5, 1810014B01Rik, and 2700046G09Rik were chosen for further analysis (Table 1). An additional lncRNA was selected because of its unique chromosomal location and previously reported association to DNA methylation dynamics in the inner ear [21]. Xloc_012867 is located in the region near Gjb2, a prominent deafness-related gene [22,23] ( Table 1).…”

Section: Selection Of Functionally Relevant Inner Ear Lncrnasmentioning

confidence: 99%

Identification and characterization of key long non-coding RNAs in the mouse cochlea

Koffler-Brill

Taiber

Anaya

et al. 2020

Preprint

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Background: The auditory system is a complex sensory network with an orchestrated multilayer regulatory program governing its development and maintenance. Accumulating evidence has implicated long non-coding RNAs (lncRNAs) as important regulators in numerous systems, as well as in pathological pathways. However, their function in the auditory system has yet to be explored. Results: Using a set of specific criteria, we selected four lncRNAs that are relevant for inner ear function. Bioinformatic characterization demonstrated a lack of coding potential and an absence of evolutionary conservation that represent properties commonly shared by their class members. RNAscope analysis of the spatial and temporal expression profiles revealed specific localization to inner ear cells. Sub-cellular localization analysis presented a distinct pattern for each lncRNA and mouse tissue expression evaluation displayed a large variability in terms of level and location. Conclusions: Our findings establish the expression of specific lncRNAs in different cell types of the auditory system and present a potential pathway by which the lncRNA Gas5 acts in the inner ear. Studying lncRNAs and deciphering their functions may deepen our knowledge of inner ear physiology and morphology and may reveal the basis of as yet unresolved genetic hearing loss-related pathologies. Moreover, our experimental design may be employed as a reference for studying other inner ear-related lncRNAs, as well as lncRNAs expressed in other sensory systems.

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“…Motivated by the TF motifs effect on local DNA methylation profiles, we further investigated the conservation of TF binding across different cell types. As DNA methylation plays an essential role in embryonic development and methylation is relatively high at the whole genome level compared to other cells ( Felsenfeld and Bell, 2000 ; Altun et al, 2010 ; Singer et al, 2014 ; Yizhar-Barnea et al, 2018 ), we used h1-hESC as the control group. Then we ordered the methylation levels of TF bound regions in H1-hESC cells and overlapped the regions in other cell lines.…”

Section: Resultsmentioning

confidence: 99%

Effects of DNA Methylation on TFs in Human Embryonic Stem Cells

et al. 2021

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DNA methylation is an important epigenetic mechanism for gene regulation. The conventional view of DNA methylation is that DNA methylation could disrupt protein-DNA interactions and repress gene expression. Several recent studies reported that DNA methylation could alter transcription factors (TFs) binding sequence specificity in vitro. Here, we took advantage of the large sets of ChIP-seq data for TFs and whole-genome bisulfite sequencing data in many cell types to perform a systematic analysis of the protein-DNA methylation in vivo. We observed that many TFs could bind methylated DNA regions, especially in H1-hESC cells. By locating binding sites, we confirmed that some TFs could bind to methylated CpGs directly. The different proportion of CpGs at TF binding specificity motifs in different methylation statuses shows that some TFs are sensitive to methylation and some could bind to the methylated DNA with different motifs, such as CEBPB and CTCF. At the same time, TF binding could interactively alter local DNA methylation. The TF hypermethylation binding sites extensively overlap with enhancers. And we also found that some DNase I hypersensitive sites were specifically hypermethylated in H1-hESC cells. At last, compared with TFs’ binding regions in multiple cell types, we observed that CTCF binding to high methylated regions in H1-hESC were not conservative. These pieces of evidence indicate that TFs that bind to hypermethylation DNA in H1-hESC cells may associate with enhancers to regulate special biological functions.

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DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory sensory epithelium

Cited by 28 publications

References 78 publications

Open chromatin dynamics in prosensory cells of the embryonic mouse cochlea

Open chromatin dynamics in prosensory cells of the embryonic mouse cochlea

Identification and characterization of key long non-coding RNAs in the mouse cochlea

Effects of DNA Methylation on TFs in Human Embryonic Stem Cells

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