Genomic imprinting is regulated by parental-specific DNA methylation of imprinting control regions (ICRs). Despite an identical DNA sequence, ICRs can exist in two distinct epigenetic states that are memorized throughout unlimited cell divisions and reset during germline formation. Here, we systematically study the genetic and epigenetic determinants of this epigenetic bistability. By iterative integration of ICRs and related DNA sequences to an ectopic location in the mouse genome, we first identify the DNA sequence features required for maintenance of epigenetic states in embryonic stem cells. The autonomous regulatory properties of ICRs further enabled us to create DNA-methylation-sensitive reporters and to screen for key components involved in regulating their epigenetic memory. Besides DNMT1, UHRF1 and ZFP57, we identify factors that prevent switching from methylated to unmethylated states and show that two of these candidates, ATF7IP and ZMYM2, are important for the stability of DNA and H3K9 methylation at ICRs in embryonic stem cells.
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http://dx.doi.org/10.1038/s41588-022-01210-z | DOI Listing |
BMC Genomics
January 2025
Shanghai Key Laboratory of Plant Functional Genomics and Resources, Shanghai Chenshan Botanical Garden, No. 3888 Chenhua Road, Songjiang District, Shanghai, 201602, China.
Background: Despite the rapid advancement of high-throughput sequencing, simple sequence repeats (SSRs) remain indispensable molecular markers for various applied and research tasks owing to their cost-effectiveness and ease of use. However, existing SSR markers cannot meet the growing demand for research on lotus (Nelumbo Adans.) given their scarcity and weak connections to the lotus genome.
View Article and Find Full Text PDFNat Struct Mol Biol
January 2025
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Transcription factors (TFs) recognize specific bases within their DNA-binding motifs, with each base contributing nearly independently to total binding energy. However, the energetic contributions of particular dinucleotides can deviate strongly from the additive approximation, indicating that some TFs can specifically recognize DNA dinucleotides. Here we solved high-resolution (<1 Å) structures of MYF5 and BARHL2 bound to DNAs containing sets of dinucleotides that have different affinities to the proteins.
View Article and Find Full Text PDFAm J Hum Genet
January 2025
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Each human genome has approximately 5 million DNA variants. Even for complete loss-of-function variants causing inherited, monogenic diseases, current understanding based on gene-specific molecular function does not adequately predict variability observed between people with identical mutations or fluctuating disease trajectories. We present a parallel paradigm for loss-of-function variants based on broader consequences to the cell when aberrant polypeptide chains of amino acids are translated from mutant RNA to generate mutated proteins.
View Article and Find Full Text PDFAm J Hum Genet
January 2025
Key Laboratory of Biomedical Information Engineering of Ministry of Education, Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions, Biomedical Informatics & Genomics Center, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, Shaanxi, China. Electronic address:
Central obesity is associated with higher risk of developing a wide range of diseases independent of overall obesity. Genome-wide association studies (GWASs) have identified more than 300 susceptibility loci associated with central obesity. However, the functional understanding of these loci is limited by the fact that most loci are in non-coding regions.
View Article and Find Full Text PDFMol Cell
January 2025
State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Tsinghua-Peking Joint Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China. Electronic address:
In a recent issue of Cell, Arribas et al. and Pasquesi et al. explore the phenomenon of transposable element (TE) exonization and its impact on proteomic and immune diversity, highlighting its potential role as a driver of evolutionary innovation.
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