Sexually Dimorphic Transcriptomic Changes of Developing Fetal Brain Reveal Signaling Pathways and Marker Genes of Brain Cells in Domestic Pigs

Strawn, Monica; Moraes, J.G.N.; Safranski, Timothy J.; Behura, Susanta K.

doi:10.3390/cells10092439

Cited by 12 publications

(16 citation statements)

References 90 publications

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“…RNA-seq data analysis was performed as described in our earlier studies. 41,42 Briefly, the quality of raw sequences was checked with FastQC followed by trimming the adaptors from the sequence reads by cutadapt. The fqtrim tool was used to perform base quality trimming (Phred score > 30) by sliding window scan (6 nucleotides).…”

Section: Rna-seq Data Analysismentioning

confidence: 99%

“…41 We also showed that specific genes are regulated in a sex-bias manner during fetal brain development in pigs. 42 Furthermore, studies by others have shown that epigenetic and metabolic changes in the fetal brain can impact overall health later in life, 34,35 particularly in the context of declining metabolism in the brain. 36,37 However, the epigenetic connection between the development and aging of the brain remains poorly studied.…”

Section: Introductionmentioning

confidence: 99%

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Fetal origin of sex‐bias brain aging

2022

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DNA methylation plays crucial roles during fetal development as well as aging. Whether the aging of the brain is programmed at the fetal stage remains untested. To test this hypothesis, mouse epigenetic clock (epiclock) was profiled in fetal (gestation day 15), postnatal (day 5), and aging (week 70) brain of male and female C57BL/6J inbred mice. Data analysis showed that on week 70, the female brain was epigenetically younger than the male brain. Predictive modeling by neural network identified specific methylations in the brain at the developing stages that were predictive of epigenetic state of the brain during aging. Transcriptomic analysis showed coordinated changes in the expression of epiclock genes in the fetal brain relative to the placenta. Whole‐genome bisulfite sequencing identified sites that were methylated both in the placenta and fetal brain in a sex‐specific manner. Epiclock genes and genes associated with specific signaling pathways, primarily the gonadotropin‐releasing hormone receptor (GnRHR) pathway, were associated with the sex‐bias methylations in the placenta as well as the fetal brain. Transcriptional crosstalk among the epiclock and GnRHR pathway genes was evident in the placenta that was maintained in the brain during development as well as aging. Collectively, these findings suggest that sex differences in the aging of the brain are of fetal origin and epigenetically linked to the placenta.

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Section: Rna-seq Data Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fetal origin of sex‐bias brain aging

2022

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“…In addition, we also found evidences for differential expression of specific aging genes in the male and female fetal brain in response to ablation of uterine Foxa2 , an essential gene required for pregnancy establishment (37). We also showed that specific genes are regulated in a sex-bias manner during fetal brain development in pigs (38). Furthermore, studies by others have shown that epigenetic and metabolic changes in the fetal brain can impact overall health later in life (34, 35) particularly in the context of declining metabolism in the brain (36, 37).…”

Section: Introductionmentioning

confidence: 66%

“…RNA-seq data analysis was performed as described in our earlier studies (37, 38). Briefly, the quality of raw sequences was checked with FastQC followed by trimming the adaptors from the sequence reads by cutadapt .…”

Section: Methodsmentioning

confidence: 99%

Fetal origin of sex-bias brain aging

Islam

Strawn

Behura

2022

Preprint

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DNA methylation plays crucial roles during fetal development as well as aging. Whether the aging of the brain is programmed at the fetal stage remains untested. To test this hypothesis, mouse epigenetic clock (epiclock) was profiled in fetal (gestation day 15), postnatal (day 5), and aging (week 70) brain of male and female C57BL/6J inbred mice. Data analysis showed that on week 70 the female brain was epigenetically younger than the male brain. Predictive modeling by neural network identified specific methylations in the brain at the developing stages that were predictive of epigenetic state of the brain during aging. Transcriptomic analysis showed coordinated changes in expression of epiclock genes in the fetal brain relative to placenta. Whole-genome bisulfite sequencing identified sites that were methylated both in the placenta and fetal brain in a sex-specific manner. Epiclock genes and genes associated with specific signaling pathways, primarily the gonadotropin-releasing hormone receptor (GnRHR) pathway, were associated with these sex-bias methylations in the placenta as well as fetal brain. Transcriptional crosstalk among the epiclock and GnRHR pathway genes was evident in the placenta that was maintained in the brain during development as well as aging. Collectively, these findings suggest that sex differences in the aging of brain are of fetal origin and epigenetically linked to the placenta.

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“…Each library was sequenced to 20 million paired end reads of 150 bases using a NovaSeq sequencer. RNA-seq data analysis was performed as described in our earlier works (108, 120). Briefly, the quality of raw sequences was checked with FastQC followed by trimming the adaptors from the sequence reads by cutadapt .…”

Section: Methodsmentioning

confidence: 99%

Role of Caveolin 1 in metabolic programming of fetal brain

Islam

Behura

2022

Preprint

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Caveolin-1 (Cav1) encodes a major protein of the lipid rafts, called caveolae, which are plasma membrane invaginations found in most cells of mammals. Cav1-null mice, at an early adult age, exhibit symptoms that are hallmarks of Alzheimers disease, and show brain aging similar to that of one and half year old wildtype mice. In the present study, integrative analysis of metabolomics, transcriptomics, epigenetics and single cell data was performed to test the hypothesis that metabolic deregulation of fetal brain due to lack of Cav1 influenced brain aging in these mice. The results of this study show that lack of Cav1 deregulated lipid and amino acid metabolism in the fetal brain. Genes associated with the deregulated metabolites were significantly altered in specific glial cells of the fetal brain, and epigenetically altered in a coordinated manner with specific genes of mouse epigenetic clock. The interaction between metabolic and epigenetic changes in the fetal brain altered gene expression of the brain at old age. Together, these results suggested that metabolic deregulation in the fetal life elicited an epigenetic memory that altered brain programming for aging in Cav1-null mice.

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Sexually Dimorphic Transcriptomic Changes of Developing Fetal Brain Reveal Signaling Pathways and Marker Genes of Brain Cells in Domestic Pigs

Cited by 12 publications

References 90 publications

Fetal origin of sex‐bias brain aging

Fetal origin of sex‐bias brain aging

Fetal origin of sex-bias brain aging

Role of Caveolin 1 in metabolic programming of fetal brain

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