'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Wed, 06 Dec 2023 02:34:39 EST Wed, 06 Dec 2023 02:34:39 EST jirtle@radonc.duke.edu james001@jirtle.com Nutrigenomics and redox regulation: Concepts relating to the Special Issue on nutrigenomics. Klotz LO, Carlberg C
Redox Biol (Dec 2023)

During our whole lifespan, from conception to death, the epigenomes of all tissues and cell types of our body integrate signals from the environment. This includes signals derived from our diet and the uptake of macro- and micronutrients. In most cases, this leads only to transient changes, but some effects of this epigenome programming process are persistent and can even be transferred to the next generation. Both epigenetic programming and redox processes are affected by the individual choice of diet and other lifestyle decisions like physical activity. The nutrient-gene communication pathways have adapted during human evolution and are essential for maintaining health. However, when they are maladaptive, such as in long-term obesity, they significantly contribute to diseases like type 2 diabetes and cancer. The field of nutrigenomics investigates nutrition-related signal transduction pathways and their effect on gene expression involving interactions both with the genome and the epigenomes. Several of these diet-(epi)genome interactions and the involved signal transduction cascades are redox-regulated. Examples include the effects of the NAD/NADH ratio, vitamin C levels and secondary metabolites of dietary molecules from plants on the acetylation and methylation state of the epigenome as well as on gene expression through redox-sensitive pathways via the transcription factors NFE2L2 and FOXO. In this review, we summarize and extend on these topics as well as those discussed in the articles of this Special Issue and take them into the context of redox biology.]]> Wed, 31 Dec 1969 19:00:00 EST Multi-omics analysis in developmental bone biology. Matsushita Y, Noguchi A, Ono W, Ono N
Jpn Dent Sci Rev (Dec 2023)

Single-cell omics and multi-omics have revolutionized our understanding of molecular and cellular biological processes at a single-cell level. In bone biology, the combination of single-cell RNA-sequencing analyses and in vivo lineage-tracing approaches has successfully identified multi-cellular diversity and dynamics of skeletal cells. This established a new concept that bone growth and regeneration are regulated by concerted actions of multiple types of skeletal stem cells, which reside in spatiotemporally distinct niches. One important subtype is endosteal stem cells that are particularly abundant in young bone marrow. The discovery of this new skeletal stem cell type has been facilitated by single-cell multi-omics, which simultaneously measures gene expression and chromatin accessibility. Using single-cell omics, it is now possible to computationally predict the immediate future state of individual cells and their differentiation potential. In vivo validation using histological approaches is the key to interpret the computational prediction. The emerging spatial omics, such as spatial transcriptomics and epigenomics, have major advantage in retaining the location of individual cells within highly complex tissue architecture. Spatial omics can be integrated with other omics to further obtain in-depth insights. Single-cell multi-omics are now becoming an essential tool to unravel intricate multicellular dynamics and intercellular interactions of skeletal cells.]]> Wed, 31 Dec 1969 19:00:00 EST Adrenergic and mesenchymal signatures are identifiable in cell-free DNA and correlate with metastatic disease burden in children with neuroblastoma. Vayani OR, Kaufman ME, Moore K, Chennakesavalu M, TerHaar R, Chaves G, Chlenski A, He C, Cohn SL, Applebaum MA
Pediatr Blood Cancer (Jan 2024)

Cell-free DNA (cfDNA) profiles of 5-hydroxymethylcytosine (5-hmC), an epigenetic marker of open chromatin and active gene expression, are correlated with metastatic disease burden in patients with neuroblastoma. Neuroblastoma tumors are comprised of adrenergic (ADRN) and mesenchymal (MES) cells, and the relative abundance of each in tumor biopsies has prognostic implications. We hypothesized that ADRN and MES-specific signatures could be quantified in cfDNA 5-hmC profiles and would augment the detection of metastatic burden in patients with neuroblastoma.]]> Wed, 31 Dec 1969 19:00:00 EST DNA methylation biomarkers to identify epigenetically abnormal spermatozoa in male partners from couples experiencing recurrent pregnancy loss. Khambata K, Begum S, Raut S, Mohan S, Irani D, Singh D, Bansal V, Patil A, Balasinor NH
Epigenetics (Dec 2023)

Previously, we showed that DNA methylation defects in spermatozoa from male partners of couples undergoing recurrent pregnancy loss (RPL) could be a contributing paternal factor. In the present study, we aimed to determine whether the methylation levels of selected imprinted genes can be used as diagnostic markers to identify epigenetically abnormal spermatozoa sample in these cases. The methylation levels of selected imprinted genes in spermatozoa, which were previously found to be differentially methylated, were combined into a probability score (between 0-1) using multiple logistic regression. Different combinations of these genes were investigated using Receiver Operating Characteristic analysis, and the threshold values were experimentally validated in an independent cohort of 38 control and 45 RPL spermatozoa samples. Among the different combinations investigated, a combination of five imprinted genes comprising IGF2-H19 DMR, IG-DMR, ZAC, KvDMR, and PEG3 (AUC = 0.88) with a threshold value of 0.61 was selected with a specificity of 90.41% and sensitivity of 70%. The results from the validation study indicated that 97% of the control samples had probability scores below this threshold, whereas 40% of the RPL samples were above this threshold with a post-hoc power of 97.8%. Thus, this combination can correctly classify control samples and potentially identify epigenetically abnormal spermatozoa samples in the male partners of couples undergoing RPL. We propose that the combined DNA methylation levels of these imprinted genes can be used as a diagnostic tool to identify spermatozoa samples with epigenetic defects which could contribute to the pathophysiology of RPL and the couple could be counselled appropriately.]]> Wed, 31 Dec 1969 19:00:00 EST Canonical transcriptional gene silencing may contribute to long-term heat response and recovery through MOM1. Torres JR, Botto JF, Sanchez DH
Plant Cell Environ (Jan 2024)

Plant canonical transcriptional gene silencing (TGS) is involved in epigenetic mechanisms that mediate genomic imprinting and the suppression of transposable elements (TEs). It has been recognised that long-term heat disrupts epigenetic silencing, with the ensuing activation of TEs. However, the physiological involvement of the TGS machinery under prolonged high temperatures has not yet been established. Here, we performed non-lethal extended periodic heat stress and recovery treatments on Arabidopsis thaliana lines mutated on key TGS factors, analysing transcriptomic changes of coding-protein genes and TEs. Plants bearing MET1, DRM2 and CMT3, and MOM1 mutated alleles showed novel transcriptional properties compatible with functionalities concerning the induction/repression of partially shared or private heat-triggered transcriptome networks. Certain observations supported the idea that some responses are based on thermal de-silencing. TEs transcriptional activation uncovered the interaction with specific epigenetic layers, which may play dedicated suppressing roles under determinate physiological conditions such as heat. Furthermore, physiological experimentation suggested that MOM1 is required to resume growth after stress. Our data thus provide initial evidence that at least one canonical TGS factor may contribute to plant acclimation and recovery from non-lethal long-term heat despite the stress-induced epigenetic disturbance.]]> Wed, 31 Dec 1969 19:00:00 EST Clinical, genomic, and epigenomic analyses of H3K27M-mutant diffuse midline glioma long-term survivors reveal a distinct group of tumors with MAPK pathway alterations. Roberts HJ, Ji S, Picca A, Sanson M, Garcia M, Snuderl M, Schüller U, Picart T, Ducray F, Green AL, Nakano Y, Sturm D, Abdullaev Z, Aldape K, Dang D, Kumar-Sinha C, Wu YM, Robinson D, Vo JN, Chinnaiyan AM, Cartaxo R, Upadhyaya SA, Mody R, Chiang J, Baker S, Solomon D, Venneti S, Pratt D, Waszak SM, Koschmann C
Acta Neuropathol (Dec 2023)

]]> Wed, 31 Dec 1969 19:00:00 EST Cleavage Under Targets & Release Using Nuclease (CUT&RUN) of Histone Modifications in Epidermal Stem Cells of Adult Murine Skin. Flora P, Ezhkova E
Methods Mol Biol (2024)

Cleavage Under Targets & Release Using Nuclease (CUT&RUN) has swiftly become the preferred procedure over the past few years for genomic mapping and detecting interactions between chromatin and its bound proteins. CUT&RUN is now being widely used for characterizing the epigenetic landscape in many cell types as it utilizes far less cell numbers when compared to Chromatin Immunoprecipitation-sequencing (ChIP-seq), thereby making it a powerful tool for researchers working with limited material. This protocol has been specifically optimized for detecting histone modifications in fluorescence-activated cell sorting (FACS)-isolated epidermal stem cells from adult mice.]]> Wed, 31 Dec 1969 19:00:00 EST A consistent pattern of slide effects in Illumina DNA methylation BeadChip array data. Hecker J, Lee S, Kachroo P, Prokopenko D, Maaser-Hecker A, Lutz SM, Hahn G, Irizarry R, Weiss ST, DeMeo DL, Lange C
Epigenetics (Dec 2023)

Recent studies have identified thousands of associations between DNA methylation CpGs and complex diseases/traits, emphasizing the critical role of epigenetics in understanding disease aetiology and identifying biomarkers. However, association analyses based on methylation array data are susceptible to batch/slide effects, which can lead to inflated false positive rates or reduced statistical power We use multiple DNA methylation datasets based on the popular Illumina Infinium MethylationEPIC BeadChip array to describe consistent patterns and the joint distribution of slide effects across CpGs, confirming and extending previous results. The susceptible CpGs overlap with the Illumina Infinium HumanMethylation450 BeadChip array content. Our findings reveal systematic patterns in slide effects. The observations provide further insights into the characteristics of these effects and can improve existing adjustment approaches.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenetic modification related to cognitive changes during a cognitive training intervention in depression. Van Assche E, Hohoff C, Zang J, Knight MJ, Baune BT
Prog Neuropsychopharmacol Biol Psychiatry (Dec 2023)

DNA methylation as a biomarker is well suited to investigate dynamic processes, such as symptom improvement. For this study we focus on epigenomic state or trait markers as early signatures of cognitive improvement in individuals receiving a cognitive intervention. We performed a first epigenome-wide association study (EWAS) on patients with cognitive dysfunction in depression comparing those with vs without cognitive dysfunction and those cognitively improving vs non-improving following a cognitive intervention.]]> Wed, 31 Dec 1969 19:00:00 EST Evolutionary insights into 3D genome organization and epigenetic landscape of . Junaid A, Singh B, Bhatia S
Life Sci Alliance (Jan 2024)

Eukaryotic genomes show an intricate three-dimensional (3D) organization within the nucleus that regulates multiple biological processes including gene expression. Contrary to animals, understanding of 3D genome organization in plants remains at a nascent stage. Here, we investigate the evolution of 3D chromatin architecture in legumes. By using cutting-edge PacBio, Illumina, and Hi-C contact reads, we report a gap-free, chromosome-scale reference genome assembly of , an important minor legume cultivated in Southeast Asia. We spatially resolved chromosomes into euchromatic, transcriptionally active A compartment and heterochromatic, transcriptionally-dormant B compartment. We report the presence of TAD-like-regions throughout the diagonal of the HiC matrix that resembled transcriptional quiescent centers based on their genomic and epigenomic features. We observed high syntenic breakpoints but also high coverage of syntenic sequences and conserved blocks in boundary regions than in the TAD-like region domains. Our findings present unprecedented evolutionary insights into spatial 3D genome organization and epigenetic patterns and their interaction within the genome. This will aid future genomics and epigenomics research and breeding programs of .]]> Wed, 31 Dec 1969 19:00:00 EST Epigenomics in aortic dissection: From mechanism to therapeutics. Tao Y, Li G, Yang Y, Wang Z, Wang S, Li X, Yu T, Fu X
Life Sci (Dec 2023)

Aortic dissection (AD) has an unfavorable prognosis. It requires early diagnosis, appropriate treatment strategies, and suspicion to recognize symptoms; thus, it is commonly described as an acute aortic emergency. The clinical manifestations of painless AD are complex and variable. However, there is no effective treatment to prevent the progression of AD. Therefore, study of the molecular targets and mechanisms of AD to enable prevention or early intervention is particularly important. Although multiple gene mutations have been proposed as linked to AD development, evidence that multiple epigenetic elements are strongly associated is steadily increasing. These epigenetic processes include DNA methylation, N6-methyladenosine, histone modification, non-histone posttranslational modification, and non-coding RNAs (ncRNAs). Among these processes, resveratrol targeting Sirtuin 1 (SIRT1), 5-azacytidine (5azaC) targeting DNA methyltransferase (DNMT), and vitamin C targeting ten-eleven translocation 2 (Tet2) showed unique advantages in improving AD and vascular dysfunction. Finally, we explored potential epigenetic drugs and diagnostic methods for AD, which might provide options for the future.]]> Wed, 31 Dec 1969 19:00:00 EST Altered expression of imprinted genes in patients with cytogenetically normal‑acute myeloid leukemia: Implications for leukemogenesis and survival outcomes. Yang MY, Hsu CM, Lin PM, Yang CH, Hu ML, Chen IY, Lin SF
Mol Clin Oncol (Dec 2023)

Genomic imprinting, an epigenetic mechanism that regulates gene expression from parental chromosomes, holds substantial relevance in multiple cancers, including hematopoietic malignancies. In the present study, the expression of a panel of 16 human imprinted genes in bone marrow samples from 64 patients newly diagnosed with cytogenetically normal-acute myeloid leukemia (CN-AML) were examined alongside peripheral blood samples from 85 healthy subjects. The validated findings of the present study revealed significant upregulation of seven genes [COPI coat complex subunit gamma 2 (), H19 imprinted maternally expressed transcript (), insulin like growth factor 2 (), PEG3 antisense RNA 1 (), DNA primase subunit 2 (), solute carrier family 22 member 3 and Zinc finger protein 215 ()] in patients with CN-AML (P<0.001). Notably, the expression level of exhibited an inverse association with the survival duration of the patients (P=0.018), establishing it as a predictive marker for two- and five-year survival in patients with CN-AML. Kaplan-Meier analysis demonstrated that patients with lower expression had superior two- and five-year survival rates compared with those with higher expression. The results of the present study highlighted the association between loss of imprinting and leukemogenesis in CN-AML, underscoring the significance of imprinting loss as a prognostic indicator for unfavorable two- and five-year survival in CN-AML patients.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa. Jin L, Chen Y, Muzaffar S, Li C, Mier-Aguilar CA, Khan J, Kashyap MP, Liu S, Srivastava R, Deshane JS, Townes TM, Elewski BE, Elmets CA, Crossman DK, Raman C, Athar M
Proc Natl Acad Sci U S A (Dec 2023)

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by // and family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49f cells. The disruption of the enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.]]> Wed, 31 Dec 1969 19:00:00 EST Involvement of CCCTC-binding factor in epigenetic regulation of cancer. Bose S, Saha S, Goswami H, Shanmugam G, Sarkar K
Mol Biol Rep (Dec 2023)

A major global health burden continues to be borne by the complex and multifaceted disease of cancer. Epigenetic changes, which are essential for the emergence and spread of cancer, have drawn a huge amount of attention recently. The CCCTC-binding factor (CTCF), which takes part in a wide range of cellular processes including genomic imprinting, X chromosome inactivation, 3D chromatin architecture, local modifications of histone, and RNA polymerase II-mediated gene transcription, stands out among the diverse array of epigenetic regulators. CTCF not only functions as an architectural protein but also modulates DNA methylation and histone modifications. Epigenetic regulation of cancer has already been the focus of plenty of studies. Understanding the role of CTCF in the cancer epigenetic landscape may lead to the development of novel targeted therapeutic strategies for cancer. CTCF has already earned its status as a tumor suppressor gene by acting like a homeostatic regulator of genome integrity and function. Moreover, CTCF has a direct effect on many important transcriptional regulators that control the cell cycle, apoptosis, senescence, and differentiation. As we learn more about CTCF-mediated epigenetic modifications and transcriptional regulations, the possibility of utilizing CTCF as a diagnostic marker and therapeutic target for cancer will also increase. Thus, the current review intends to promote personalized and precision-based therapeutics for cancer patients by shedding light on the complex interplay between CTCF and epigenetic processes.]]> Wed, 31 Dec 1969 19:00:00 EST High-capacity sample multiplexing for single cell chromatin accessibility profiling. Booth GT, Daza RM, Srivatsan SR, McFaline-Figueroa JL, Gladden RG, Mullen AC, Furlan SN, Shendure J, Trapnell C
BMC Genomics (Dec 2023)

Single-cell chromatin accessibility has emerged as a powerful means of understanding the epigenetic landscape of diverse tissues and cell types, but profiling cells from many independent specimens is challenging and costly. Here we describe a novel approach, sciPlex-ATAC-seq, which uses unmodified DNA oligos as sample-specific nuclear labels, enabling the concurrent profiling of chromatin accessibility within single nuclei from virtually unlimited specimens or experimental conditions. We first demonstrate our method with a chemical epigenomics screen, in which we identify drug-altered distal regulatory sites predictive of compound- and dose-dependent effects on transcription. We then analyze cell type-specific chromatin changes in PBMCs from multiple donors responding to synthetic and allogeneic immune stimulation. We quantify stimulation-altered immune cell compositions and isolate the unique effects of allogeneic stimulation on chromatin accessibility specific to T-lymphocytes. Finally, we observe that impaired global chromatin decondensation often coincides with chemical inhibition of allogeneic T-cell activation.]]> Wed, 31 Dec 1969 19:00:00 EST Histopathologic brain age estimation via multiple instance learning. Marx GA, Kauffman J, McKenzie AT, Koenigsberg DG, McMillan CT, Morgello S, Karlovich E, Insausti R, Richardson TE, Walker JM, White CL, Babrowicz BM, Shen L, McKee AC, Stein TD,  , Farrell K, Crary JF
Acta Neuropathol (Dec 2023)

Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as elucidate pathological determinants of age-related functional decline and identify early disease changes in the context of Alzheimer's and other disorders. Histopathological whole slide images provide a wealth of pathologic data on the cellular level that can be leveraged to build deep learning models to assess age acceleration. Here, we used a collection of digitized human post-mortem hippocampal sections to develop a histological brain age estimation model. Our model predicted brain age within a mean absolute error of 5.45 ± 0.22 years, with attention weights corresponding to neuroanatomical regions vulnerable to age-related changes. We found that histopathologic brain age acceleration had significant associations with clinical and pathologic outcomes that were not found with epigenetic based measures. Our results indicate that histopathologic brain age is a powerful, independent metric for understanding factors that contribute to brain aging.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenetic programming for obesity and noncommunicable disease: From womb to tomb. Saavedra LPJ, Piovan S, Moreira VM, Gonçalves GD, Ferreira ARO, Ribeiro MVG, Peres MNC, Almeida DL, Raposo SR, da Silva MC, Barbosa LF, de Freitas Mathias PC
Rev Endocr Metab Disord (Dec 2023)

Several epidemiological, clinical and experimental studies in recent decades have shown the relationship between exposure to stressors during development and health outcomes later in life. The characterization of these susceptible phases, such as preconception, gestation, lactation and adolescence, and the understanding of factors that influence the risk of an adult individual for developing obesity, metabolic and cardiovascular diseases, is the focus of the DOHaD (Developmental Origins of Health and Disease) research line. In this sense, advancements in molecular biology techniques have contributed significantly to the understanding of the mechanisms underlying the observed phenotypes, their morphological and physiological alterations, having as a main driving factor the epigenetic modifications and their consequent modulation of gene expression. The present narrative review aimed to characterize the different susceptible phases of development and associated epigenetic modifications, and their implication in the development of non-communicable diseases. Additionally, we provide useful insights into interventions during development to counteract or prevent long-term programming for disease susceptibility.]]> Wed, 31 Dec 1969 19:00:00 EST Dynamics of imprinted genes and their epigenetic mechanisms in castor bean seed with persistent endosperm. Han B, Li Y, Wu D, Li DZ, Liu A, Xu W
New Phytol (Dec 2023)

Genomic imprinting refers to parent-of-origin-dependent gene expression and primarily occurs in the endosperm of flowering plants, but its functions and epigenetic mechanisms remain to be elucidated in eudicots. Castor bean, a eudicot with large and persistent endosperm, provides an excellent system for studying the imprinting. Here, we identified 131 imprinted genes in developing endosperms and endosperm at seed germination phase of castor bean, involving into the endosperm development, accumulation of storage compounds and specially seed germination. Our results showed that the transcriptional repression of maternal allele of DNA METHYLTRANSFERASE 1 (MET1) may be required for maternal genome demethylation in the endosperm. DNA methylation analysis showed that only a small fraction of imprinted genes was associated with allele-specific DNA methylation, and most of them were closely associated with constitutively unmethylated regions (UMRs), suggesting a limited role for DNA methylation in controlling genomic imprinting. Instead, histone modifications can be asymmetrically deposited in maternal and paternal genomes in a DNA methylation-independent manner to control expression of most imprinted genes. These results expanded our understanding of the occurrence and biological functions of imprinted genes and showed the evolutionary flexibility of the imprinting machinery and mechanisms in plants.]]> Wed, 31 Dec 1969 19:00:00 EST IGF2 is upregulated by its antisense RNA to potentiate pancreatic cancer progression. Tian Y, Han W, Fu L, Zhang J, Zhou X
Funct Integr Genomics (Dec 2023)

Pancreatic cancer is a deadly cancer. More and more long noncoding RNAs (lncRNAs) have received confirmation to be dysregulated in tumors and exert the regulatory function. Studies have suggested that lncRNA insulin-like growth factor 2 antisense RNA (IGF2-AS) participates in the development of some cancers. Thus, we attempted to clarify its function in pancreatic cancer. Reverse-transcription quantitative polymerase chain reaction was applied for testing IGF2-AS expression in pancreatic cancer cells. Colony formation and Transwell wound experiments were applied for determining cell proliferative, migratory, and invasive capabilities. The alteration of epithelial-mesenchymal transition (EMT)-related gene level was tested via western blot. The mice model was established for measuring the tumor growth and metastasis. RIP validated the interaction of RNAs. IGF2-AS displays high expression in pancreatic cancer cells. IGF2-AS depletion repressed PC cell proliferative, migratory, invasive capabilities, and EMT process. Furthermore, pancreatic cancer tumor growth and metastasis were also inhibited by IGF2-AS depletion. Additionally, IGF2-AS positively regulated IGF2 level via recruiting HNRNPC. IGF2 overexpression counteracted the functions of IGF2-AS deficiency on pancreatic cancer cell behaviors. Moreover, IGF2R deletion was found to inhibit the positive effect of IGF2 on pancreatic cancer progression. IGF2-AS potentiates pancreatic cancer cell proliferation, tumor growth, and metastasis by recruiting HNRNPC via the IGF2-IGF2R regulatory pathway. These discoveries might offer a novel insight for treatment of PC, which may facilitate targeted therapies of PC in clinical practice.]]> Wed, 31 Dec 1969 19:00:00 EST Hippocampal and peripheral blood DNA methylation signatures correlate at the gene and pathway level in a mouse model of autism. Alberca CD, Papale LA, Madrid A, Alisch RS
Hum Mol Genet (Dec 2023)

Autism spectrum disorders (ASD) are polygenic multifactorial disorders influenced by environmental factors. ASD-related differential DNA methylation has been found in human peripheral tissues, such as placenta, paternal sperm, buccal epithelium, and blood. However, these data lack direct comparison of DNA methylation levels with brain tissue from the same individual to determine the extent that peripheral tissues are surrogates for behavior-related disorders. Here, whole genome methylation profiling at all the possible sites throughout the mouse genome (>25 million) from both brain and blood tissues revealed novel insights into the systemic contributions of DNA methylation to ASD. Sixty-six differentially methylated regions (DMRs) share the same genomic coordinates in these two tissues, many of which are linked to risk genes for neurodevelopmental disorders and intellectual disabilities (e.g. Prkch, Ptn, Hcfc1, Mid1, and Nfia). Gene ontological pathways revealed a significant number of common terms between brain and blood (N = 65 terms), and nearly half (30/65) were associated with brain/neuronal development. Furthermore, seven DMR-associated genes among these terms contain methyl-sensitive transcription factor sequence motifs within the DMRs of both tissues; four of them (Cux2, Kcnip2, Fgf13, and Mrtfa) contain the same methyl-sensitive transcription factor binding sequence motifs (HES1/2/5, TBX2 and TFAP2C), suggesting DNA methylation influences the binding of common transcription factors required for gene expression. Together, these findings suggest that peripheral blood is a good surrogate tissue for brain and support that DNA methylation contributes to altered gene regulation in the pathogenesis of ASD.]]> Wed, 31 Dec 1969 19:00:00 EST