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

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

doi:10.1101/2021.05.03.442383

Cited by 3 publications

(12 citation statements)

References 66 publications

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“…our previously published data [5,34] with or without the estrous cycle information (Fig. 1A), we show that accounting for the estrous cycle, as an exemplary sexspecific factor, makes the data more interpretable and increases our ability to discover and explain sex differences.…”

Section: Introductionsupporting

confidence: 56%

“…Data To assess the importance of the estrous cycle information for the analysis of sex differences in neuroscience research, we reanalyzed our previously published data [5,34] generated in young adult (8-11 weeks old) male and female C57BL/6J mice. In females, we tracked the estrous cycle daily, for the duration of three cycles [5], and included mice in two extreme phases of the estrous cycle: proestrus (high estradiol-low progesterone) and early diestrus (low estradiol-high progesterone) that mimic human follicular and luteal phases, respectively (Fig.…”

Section: Methodsmentioning

confidence: 99%

“…CTCF loops The analysis of differential CTCF loops, identified using the Hi-C assay, is described in previous publication of this data [34]. Data were generated from fluorescence-activated nuclei sorting (FANS)-purified neuronal (NeuN +) nuclei isolated from the ventral hippocampus of proestrus females, diestrus females, and males (n = 3 biological replicates/group; tissue pooled from 2 animals/replicate).…”

Section: Methodsmentioning

confidence: 99%

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Why the estrous cycle matters for neuroscience

2022

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Background Ovarian hormone fluctuations over the rodent estrous cycle and the human menstrual cycle are known to significantly impact brain physiology and disease risk, yet this variable is largely ignored in preclinical neuroscience research, clinical studies, and psychiatric practice. Methods To assess the importance of the estrous cycle information for the analysis of sex differences in neuroscience research, we re-analyzed our previously published data with or without the estrous cycle information, giving a side-by-side comparison of the analyses of behavior, brain structure, gene expression, and 3D genome organization in female and male mice. We also examined and compared the variance of female and male groups across all neurobehavioral measures. Results We show that accounting for the estrous cycle significantly increases the resolution of the neuroscience studies and allows for: (a) identification of masked sex differences; (b) mechanistic insight(s) into the identified sex differences, across different neurobehavioral outcomes, from behavior to molecular phenotypes. We confirm previous findings that female data from either mixed- or staged-female groups are, on average, not more variable than that of males. However, we show that female variability is not, at all, predictive of whether the estrous cycle plays an important role in regulating the outcome of interest. Conclusions We argue that “bringing back” the estrous cycle variable to the main stage is important in order to enhance the resolution and quality of the data, to advance the health of women and other menstruators, and to make research more gender-inclusive. We strongly encourage the neuroscience community to incorporate the estrous cycle information in their study design and data analysis, whenever possible, and we debunk some myths that tend to de-emphasize the importance and discourage the inclusion of this critically important biological variable. Highlights Ovarian hormone fluctuation impacts brain physiology and is a major psychiatric risk factor, yet this variable has been overlooked in neuroscience research and psychiatric practice. From rodent behavior to gene regulation, accounting for the estrous cycle increases the resolution of the neuroscience data, allowing identification and mechanistic insight(s) into sex differences. Female variability does not equal (and is not predictive of) the estrous cycle effect and should not be used as a proxy for the effects of ovarian hormones on the outcome of interest. Neuroscience researchers are advised to incorporate the estrous cycle information in their studies to foster more equitable, female- and gender-inclusive research. Studies of the ovarian cycle are especially important for improving women’s mental health.

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Section: Introductionsupporting

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Why the estrous cycle matters for neuroscience

2022

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“…Note that the Hi-C data and DNA methylation data were not from matched samples, but two different cohorts. However, these results suggest that although we found DNAme to not be predictive of sex differences in gene expression (Additional file 87 : Figure S5), these saDMPs may interact with other genes, transcription factors and other epigenetic modifications to direct chromatin organisation and regulatory networks.…”

Section: Discussionmentioning

confidence: 75%

Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array

et al. 2022

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Background Sex differences are known to play a role in disease aetiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood by performing a discovery (n = 1171) and validation (n = 2471) analysis. Results We identified and validated 396 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be female-biased CpGs (74%). These saDMP’s are enriched in CpG islands and CpG shores and located preferentially at 5’UTRs, 3’UTRs and enhancers. Additionally, we identified 266 significant sex-associated differentially methylated regions overlapping genes, which have previously been shown to exhibit epigenetic sex differences, and novel genes. Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and ESR1. Conclusion Our study reports a reliable catalogue of sex-associated CpG sites and elucidates several characteristics of these sites using large-scale discovery and validation data sets. This resource will benefit future studies aiming to investigate sex specific epigenetic signatures and further our understanding of the role of DNA methylation in sex differences in human whole blood.

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“…It has previously been reported that 3D genome organisation can impact sex biased gene expression through direct and indirect effects of cohesion and CTCF looping on enhancer interactions with sex biased genes (77), Recently, it was shown that with rising oestrogen levels, the female brain exhibits sex hormone driven plasticity and that chromatin changes underlie this (78). Interestingly, by annotating our saDMPs to distal genes using chromatin loops, we were able to identify contacts between saDMPs and three genes HIST1H3A, HIST1H4A and HIST1H4B which are core components of nucleosome, thereby responsible for playing a role in chromatin organisation.…”

Section: Discussionmentioning

confidence: 99%

Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array

Grant

Wang

Zabet

et al. 2021

Preprint

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Sex differences are known to play a role in disease etiology, progression and outcome. Previous studies have revealed autosomal epigenetic differences between males and females in some tissues, including differences in DNA methylation patterns. Here, we report for the first time an analysis of autosomal sex differences in DNAme using the Illumina EPIC array in human whole blood (n=1171). We identified 554 sex-associated differentially methylated CpG sites (saDMPs) with the majority found to be hypermethylated in females (70%). These saDMP's are enriched in CpG islands and CpG shores and located preferentially at 5'UTRs, 3'UTRs and enhancers. Additionally, we identified 311 significant sex associated differentially methylated regions (saDMRs). Transcription factor binding site enrichment revealed enrichment of transcription factors related to critical developmental processes and sex determination such as SRY and SOX9. Our study reports a reliable catalogue of sex associated CpG sites and elucidates several characteristics of these sites.

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

Cited by 3 publications

References 66 publications

Why the estrous cycle matters for neuroscience

Why the estrous cycle matters for neuroscience

Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array

Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array

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