Differential Regulation of Mouse Hippocampal Gene Expression Sex Differences by Chromosomal Content and Gonadal Sex

Ocañas, Sarah R.; Ansere, Victor A.; Tooley, Kyla B.; Hadad, Niran; Chucair-Elliott, Ana J.; Stanford, David R.; Rice, Shannon; Wronowski, Benjamin; Pham, Kevin D.; Hoffman, Jessica M.; Austad, Steven N.; Stout, Michael B.; Freeman, Willard M.

doi:10.1007/s12035-022-02860-0

Cited by 11 publications

(9 citation statements)

References 137 publications

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“…We then explored the interaction between genes that were differentially expressed by sex in the transcriptome and translatome of aging microglia (Figure 4C). Seven sex DEGs were identified in young and old samples from both the transcriptomic and translatomic analyses, with three being X chromosomally-encoded transcripts (Kdm6a, Eif2s3x, Xist) and four Y chromosomally-encoded (Kdm5d, Eif2s3y, Uty, Ddx3y), consistent with sexually dimorphic genes identified in previous studies from mouse hippocampus (24). Heatmaps of the relative gene expression (counts per million -CPM) showed high expression of the X-chromosomally encoded genes (Kdm6a, Eif2s3x, Xist) in females when compared to males.…”

Section: Sex Effects In the Microglial Transcriptome And Translatome ...supporting

confidence: 85%

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Ocañas

Pham

Cox

et al. 2023

Preprint

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Background Microglia, the brain's principal immune cells, have been implicated in the pathogenesis of Alzheimer's disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment that is associated with late-onset AD. Here, we examined and compared the transcriptomic and translatomic sex effects in young and old mouse hippocampus. Methods Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5-6 month-old [mo]) and old (22-25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome, respectively, for RNA-sequencing and differential expression analyses. Flow cytometry was used to confirm the transcriptomic findings. Results There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally- and autosomally-encoded sex differences emerge with aging. These sex DEGs identified at old age were primarily female-biased and were enriched in senescent and disease-associated microglial signatures. Pathway analysis identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology, and explore how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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Section: Sex Effects In the Microglial Transcriptome And Translatome ...supporting

confidence: 85%

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Ocañas

Pham

Cox

et al. 2023

Preprint

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“…While we purchased our XYT colony founders in summer 2022, the model has been commercially available following extensive backcrossing to move the FCG model onto a C57BL/6J background, completed in 2009 8 . Upregulation of the translocation genes we identified in FCG XY mice has been previously reported [11][12][13][14] , suggesting that this genetic alteration has been circulating for at least a decade.…”

Section: Main Textsupporting

confidence: 62%

Four-Core Genotypes mice harbour a 3.2MB X-Y translocation that perturbs Tlr7 dosage

Panten,

Prete,

Cleland

et al. 2023

Preprint

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The Four Core Genotypes (FCG) is a mouse model system heavily used to disentangle the function of sex chromosomes and hormones. We report that a copy of a 3.2 MB region of the X chromosome has translocated to the YSry-chromosome and thus increased the expression of multiple genes including the auto-immune master regulatorTlr7. This previously-unreported X-Y translocation complicates the interpretation of studies reliant on FCG mice.

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“…Relative gene expression levels were quantified by qPCR as previously described 63,64 . cDNA was synthesized with the ABI High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems Inc., Foster City, CA) from 25 ng of purified RNA.…”

Section: Rt-qpcrmentioning

confidence: 99%

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Kellogg

Pham

Machalinski

et al. 2023

Preprint

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Major Histocompatibility Complex I (MHC-I) function in the CNS is still being determined after previously being thought to be absent from the brain. MHC-I expression increases with brain aging in mouse, rat, and human whole tissue analyses. Neuronal MHC-I expression has been proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). However, the CNS cellular localization of MHC-I expression has been unclear. Across newly generated and publicly available ribosomal profiling, cell sorting, and single cell data, microglia were found to be the primary source of classical and non-classical MHC-I in mice and humans. TRAP-qPCR analysis of 3-6 m.o. and 18-22 m.o. mice revealed significant age-related induction of B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 in microglia but not in astrocytes and neurons. Across a timecourse from 12-23 m.o., microglial MHC-I gradually increases until 21 m.o. and then accelerates. MHC-I protein was also enriched in microglia and increased with aging. Expression of MHC-I binding Leukocyte Immunoglobulin-like (Lilr) and Paired immunoglobin-like type 2 (Pilr) receptors in microglia but not astrocytes or neurons opens the possibility of cell-autonomous signaling and are also increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in mouse AD models and human data across numerous studies and in RNA-Seq of microglia from APP-PSEN1 mice. MHC-I expression occurred concurrently with p16 suggesting an association with cellular senescence. The conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD open the possibility of cell-autonomous signaling to regulate microglial reactivation.

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Differential Regulation of Mouse Hippocampal Gene Expression Sex Differences by Chromosomal Content and Gonadal Sex

Cited by 11 publications

References 137 publications

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Four-Core Genotypes mice harbour a 3.2MB X-Y translocation that perturbs Tlr7 dosage

Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

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