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Single-cell transcriptome profiles of wild-type and IRF8KO microglia

ABSTRACT: IRF8 is a transcription factor that is crucial in determining the lineage of microglia. We previously showed that IRF8 is robustly bound during the early postnatal period. To better understand IRF8's postnatal functions, we analyzed mice in which IRF8 was removed after P16. By using single-cell nuclei sequencing, we analyzed cells in which IRF8 was definitely knocked out and investigated both the transcriptome and chromatin accessibility that IRF8 regulates. The differential analysis showed the importance of IRF8 in regulating postnatal transcriptional programs and epigenetic landscapes that are related to microglial identity and disease-associated genes. This study provides a new perspective on how IRF8-mediated transcriptional programs affect microglia.

ORGANISM(S): Mus musculus

PROVIDER: GSE266423 | GEO | 2024/07/01

REPOSITORIES: GEO

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Project description:The superior olivary complex (SOC) is a prominent auditory brainstem center and represents one of the prime model systems to study the development of sensory circuits. We recently performed genome-wide microarray studies to analyze the SOC-related genetic program at postnatal day (P)4 and P25. Here, we extended this analysis by including two additional time points, P0 and P16. Data sets were validated by qRT-PCR. Statistical analysis were performed for the different developmental time points as well as with for differences between the SOC and our previously analyzed brain samples. This analysis revealed that after hearing-onset (P16 and P25), 918 oligos were up-regulated and 810 oligos down-regulated in the SOC compared to the two prehearing stages (P0 and P4). Of the up-regulated oligos, 530 were significantly higher expressed compared to the brain at P25. Concerning neurotransmission, SOC-related elevation was mainly observed for K+ channels, G-proteins, and myelination-related proteins, whereas Ca2+-related proteins showed a decreased expression. In the pre-hearing period, 47 oligos were up-regulated compared to the brain. Several of them were transcription factors, previously associated with other auditory structures, and might ensure coordinated development of peripheral and central auditory structures. Stage-specific comparison identified distinct genetic programs during development: Circuit formation/refinement at P4; myelination and circuit refinement/consolidation at P16; and neuroprotection at P25. Altogether, our study defines the genetic program of postnatal SOC development and provides strong functional candidates for various developmental processes. The genome wide expression during the postnatal development of the SOC was investigated at two different time points: at postnatal (P) day 0 (before hearing onset) and P16 (after hearing onset). Samples were hybridized onto two color platforms. At least 6 up to nine biological replicates per sample were performed.

Project description:The superior olivary complex (SOC) is an essential auditory brainstem structure involved in sound localization. In order to identify the genetic program underlying its maturation, we profiled the transcriptome of the rat SOC at postnatal days (P)0, P4, P16, and P25, using genome-wide microarrays (41,012 sequences). Differences in gene expression between two consecutive stages were highest between P4 versus P16 (3.6%), but dropped to 0.06% between P16 versus P25. To identify SOC-related genetic programs, we also profiled the brain at P4 and P25. Differentially expressed sequences between SOC and brain almost doubled from P4 (4.4%) to P25 (7.6%). These datademonstrate considerable molecular specification around hearing onset, which is rapidly finalized. Prior to hearing onset, several transcription factors associated with the peripheral auditory system were up-regulated, likely coordinating auditory system development. Additionally, serotonin-related genes and crystalline-gamma subunits were highly expressed. The molecular repertoire of mature neurons was sculpted by SOC-related up- and down-regulation of several protein categories, among which voltage-gated channels and myelination were prominent. Comparison with the brain revealed a significant enrichment of deafness-related oligos in the SOC-related genetic program (26 in the SOC, only 11 in the brain). Furthermore, 29 out of 453 SOC-related oligos mapped within 19 genetic intervals associated with hearing impairment. Together, we identified sequential genetic programs in the SOC, thereby pinpointing candidates which may guide its development and ensure proper function. The enrichment of deafness-related genes in the SOC may have implications for restoring hearing, as central auditory structures might be more severely affected than previously appreciated. This SuperSeries is composed of the SubSeries listed below. The genome wide expression during the postnatal development of the SOC was investigated at four different time points: at postnatal (P) day 0, P4, P16 and P25. Concerning the brain, P4 and P25 were used. Samples were hybridized onto two color platforms. At least 6 up to nine biological replicates per sample were performed.

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Single-cell transcriptome profiles of wild-type and IRF8KO microglia

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