Sex-specific multi-level 3D genome dynamics in the mouse brain

Rocks, Devin; Shukla, Mamta; Ouldibbat, Laila; Finnemann, Silvia C.; Kalluchi, Achyuth; Rowley, M. Jordan; Kundaković, Marija

doi:10.1038/s41467-022-30961-w

Cited by 17 publications

(33 citation statements)

References 81 publications

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“…Analysts must be aware of how data collection by array leads to observed DNAme values, and must also consider the biological validity of downstream statistical comparisons. Similar signal-averaging effects apply to the female X chromosome signatures obtained by other genomic analysis techniques that lack allele-specificity, including but not limited to non-phased RNA sequencing, chromatin immunoprecipitation (ChIP) sequencing, and chromatin conformation studies such as Hi-C [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 93%

Who’s afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data

Inkster

Wong

Matthews

et al. 2023

Epigenetics & Chromatin

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Background Many human disease phenotypes manifest differently by sex, making the development of methods for incorporating X and Y-chromosome data into analyses vital. Unfortunately, X and Y chromosome data are frequently excluded from large-scale analyses of the human genome and epigenome due to analytical complexity associated with sex chromosome dosage differences between XX and XY individuals, and the impact of X-chromosome inactivation (XCI) on the epigenome. As such, little attention has been given to considering the methods by which sex chromosome data may be included in analyses of DNA methylation (DNAme) array data. Results With Illumina Infinium HumanMethylation450 DNAme array data from 634 placental samples, we investigated the effects of probe filtering, normalization, and batch correction on DNAme data from the X and Y chromosomes. Processing steps were evaluated in both mixed-sex and sex-stratified subsets of the analysis cohort to identify whether including both sexes impacted processing results. We found that identification of probes that have a high detection p-value, or that are non-variable, should be performed in sex-stratified data subsets to avoid over- and under-estimation of the quantity of probes eligible for removal, respectively. All normalization techniques investigated returned X and Y DNAme data that were highly correlated with the raw data from the same samples. We found no difference in batch correction results after application to mixed-sex or sex-stratified cohorts. Additionally, we identify two analytical methods suitable for XY chromosome data, the choice between which should be guided by the research question of interest, and we performed a proof-of-concept analysis studying differential DNAme on the X and Y chromosome in the context of placental acute chorioamnionitis. Finally, we provide an annotation of probe types that may be desirable to filter in X and Y chromosome analyses, including probes in repetitive elements, the X-transposed region, and cancer-testis gene promoters. Conclusion While there may be no single “best” approach for analyzing DNAme array data from the X and Y chromosome, analysts must consider key factors during processing and analysis of sex chromosome data to accommodate the underlying biology of these chromosomes, and the technical limitations of DNA methylation arrays.

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Section: Introductionmentioning

confidence: 93%

Who’s afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data

Inkster

Wong

Matthews

et al. 2023

Epigenetics & Chromatin

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“…However, molecular mechanisms that underlie these brain and behavioral dynamics have only been described in the last couple of years, representing an important and exciting new development in the field. 3,36 In this section, we will discuss recently revealed epigenetic mechanisms through which cycling ovarian hormones affect hippocampal physiology, and the efforts that have been made to link these mechanisms to steroid hormone receptor mechanisms. We start by describing estrogen and progesterone receptor signaling and their downstream effects including changes in gene expression.…”

Section: Molecular Mechanisms Underlying Sex Hormone-dependent Change...mentioning

confidence: 99%

“…We recently implicated an epigenetic mechanism, the dynamic reorganization of chromatin, in neuronal gene regulation across the estrous cycle. 3,36 Chromatin is the dynamic structure, including DNA and its associated proteins (mostly histones), which can undergo conformation changes through various mechanisms to regulate gene expression 121 (Figure 3B). Accessible or open chromatin structure within gene regulatory regions, such as promoters and enhancers, promotes the binding of transcription factors and gene activation, while closed chromatin configuration is not permissive for transcription.…”

Section: Dynamic Epigenetic Regulation In Hippocampal Neurons Across ...mentioning

confidence: 99%

Hippocampus‐based behavioral, structural, and molecular dynamics across the estrous cycle

Rocks

Kundaković

2022

J Neuroendocrinology

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The activity of neurons in the rodent hippocampus contributes to diverse behaviors, with the activity of ventral hippocampal neurons affecting behaviors related to anxiety and emotion regulation, and the activity of dorsal hippocampal neurons affecting performance in learning‐ and memory‐related tasks. Hippocampal cells also express receptors for ovarian hormones, estrogen and progesterone, and are therefore affected by physiological fluctuations of those hormones that occur over the rodent estrous cycle. In this review, we discuss the effects of cycling ovarian hormones on hippocampal physiology. Starting with behavior, we explore the role of the estrous cycle in regulating hippocampus‐dependent behaviors. We go on to detail the cellular mechanisms through which cycling estrogen and progesterone, through changes in the structural and functional properties of hippocampal neurons, may be eliciting these changes in behavior. Then, providing a basis for these cellular changes, we outline the epigenetic, chromatin regulatory mechanisms through which ovarian hormones, by binding to their receptors, can affect the regulation of behavior‐ and synaptic plasticity‐related genes in hippocampal neurons. We also highlight an unconventional role that chromatin dynamics may have in regulating neuronal function across the estrous cycle, including in sex hormone‐driven X chromosome plasticity and hormonally‐induced epigenetic priming. Finally, we discuss directions for future studies and the translational value of the rodent estrous cycle for understanding the effects of the human menstrual cycle on hippocampal physiology and brain disease risk.

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“…One intriguing example for spatial genome plasticity recently emerged from a chromosomal conformation study on ventral hippocampal neurons of the adult female brain in which they compared 3D genome plasticity across the estrous cycle, and also to the male brain. The study discovered evidence for a hormone-cycle driven decondensation of many X chromosomal domains, together with highly dynamic changes in promoter-enhancer loopings at hundreds of autosomal loci occupied by estrogen-associated transcription factors and nuclear hormone receptors [ 31 ]. Specifically, serotonin signaling and anxiety emerged as top functional pathways for these hormone cycle-sensitive chromosomal conformations [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…The study discovered evidence for a hormone-cycle driven decondensation of many X chromosomal domains, together with highly dynamic changes in promoter-enhancer loopings at hundreds of autosomal loci occupied by estrogen-associated transcription factors and nuclear hormone receptors [ 31 ]. Specifically, serotonin signaling and anxiety emerged as top functional pathways for these hormone cycle-sensitive chromosomal conformations [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

3D Genome Plasticity in Normal and Diseased Neurodevelopment

Plaza-Jennings

Valada

Akbarian

2022

Genes

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Non-random spatial organization of the chromosomal material inside the nuclei of brain cells emerges as an important regulatory layer of genome organization and function in health and disease. Here, we discuss how integrative approaches assessing chromatin in context of the 3D genome is providing new insights into normal and diseased neurodevelopment. Studies in primate (incl. human) and rodent brain have confirmed that chromosomal organization in neurons and glia undergoes highly dynamic changes during pre- and early postnatal development, with potential for plasticity across a much wider age window. For example, neuronal 3D genomes from juvenile and adult cerebral cortex and hippocampus undergo chromosomal conformation changes at hundreds of loci in the context of learning and environmental enrichment, viral infection, and neuroinflammation. Furthermore, locus-specific structural DNA variations, such as micro-deletions, duplications, repeat expansions, and retroelement insertions carry the potential to disrupt the broader epigenomic and transcriptional landscape far beyond the boundaries of the site-specific variation, highlighting the critical importance of long-range intra- and inter-chromosomal contacts for neuronal and glial function.

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Sex-specific multi-level 3D genome dynamics in the mouse brain

Cited by 17 publications

References 81 publications

Who’s afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data

Who’s afraid of the X? Incorporating the X and Y chromosomes into the analysis of DNA methylation array data

Hippocampus‐based behavioral, structural, and molecular dynamics across the estrous cycle

3D Genome Plasticity in Normal and Diseased Neurodevelopment

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