Biology subjects

Scheible, K. M.

Publications and source records attributed to Scheible, K. M..

3 recordsLinked to original sources

bioRxiv2024

Gene Regulatory Programs that Specify Age-Related Differences during Thymocyte Development

T cell development is fundamental to immune system establishment, yet how this development changes with age remains poorly understood. Here, we construct a transcriptional and epigenetic atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene regulatory programs and their link to age-related differences in phenotype and function. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern effector response and cell cycle regulation. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing as a readout to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. Altogether, our study defines transcriptional and epigenetic programs that regulate age-specific differences in T cell development.

genomics↗

bioRxiv2019

Coordinated Postnatal Trajectories of T Cells and Microbiota in Preterm and Full- term Newborns

Neonatal immune-microbiota co-development is poorly understood, yet appropriate recognition of - and response to - pathogens and commensal microbiota is critical to health. In this longitudinal study of 148 pre- and 119 full-term infants from birth through one year of age we found that postmenstrual age, or weeks from conception, not post-natal age, is the dominant factor influencing T cell and mucosal microbiota development. Numerous features of the T cell and microbiota functional development remain unexplained, however, by either age metric and are instead shaped by discrete peri- and post-natal events. Most strikingly, we establish that prenatal antibiotics or infection disrupt the normal T cell population developmental trajectory, influencing subsequent respiratory microbial colonization and predicting respiratory morbidity. In this way, early exposures imprint the postnatal immune-microbiota axis and place an infant at significant risk for respiratory morbidity in early childhood. One Sentence SummaryT cells and microbiota follow predictable, coordinated trajectories in newborns, and their coordination is an important determinant of illness in the first year. Graphical AbstractNasal and rectal microbiome was assessed weekly in the NICU, monthly post-discharge, and when respiratory illness symptoms occurred. T cells were characterized at birth (cord blood), 36-42 weeks postmenstrual age, and at 12 months. Quarterly respiratory morbidity surveys determined the 12-month outcome of persistent respiratory disease. More frequent illnesses and chronic disease outcomes occurred by one year of age if development of these systems was discordant or disrupted. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/736090v3_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1f08adeorg.highwire.dtl.DTLVardef@12d3671org.highwire.dtl.DTLVardef@151396borg.highwire.dtl.DTLVardef@190dcff_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2018

Neonate gut and respiratory microbiota: coordinated development through time and space

Background: Postnatal development of the microbiota in early life influences immunity, metabolism, neurodevelopment and long-term infant health. Microbiome development occurs at multiple body sites, each with distinct community compositions and functions. Associations between microbiota at multiple sites represent an unexplored influence on the infant microbiome. Here, we examined co-occurrence patterns of gut and respiratory microbiota in pre- and full-term infants over the first year of life, a period critical to neonatal development and risk of respiratory diseases.\n\nResults: Gut and respiratory microbiota collected as longitudinal rectal, throat and nasal samples from 38 pre-term and 44 full-term infants were first clustered into community state types (CSTs) on the basis of their composition. Multiple methods were used to relate the occurrence of CSTs to several measures of infant maturity, including gestational age (GA) at birth, week of life (WOL), and post menstrual age (PMA: equal to GA plus WOL). Manifestation of CSTs followed one of three patterns with respect to infant maturity. First, chronological: independent of infant maturity (GA) at birth, and strongly associated with post-natal age (WOL). Second, idiosyncratic: primarily dependent on maturity (GA) at birth, with persistent differences in CST occurrence between pre- and full-term infants through the first year of life. Third, convergent: CSTs appear earlier in infants with greater maturity (GA) at birth, but after a sufficient post-natal interval their occurrence in pre-term infants reaches parity with full-term infants. The composition of CSTs was highly dissimilar between different body sites, but the CST of any one body site was highly predictive of the CSTs at other body sites. There were significant associations between the abundance of individual taxa at each body site and the CSTs of the other body sites, which persisted after stringent control for the non-linear effects of infant maturity. Significant canonical correlations exist between the microbiota composition at each pair of body sites, with the strongest correlations between more proximal locations.\n\nConclusion: Cross-body site associations of developing infant microbiota suggest the importance of research and clinical practices that focus on dynamic interactions between multiple microbial communities to elucidate and promote systemic microbiota development.

developmental biology↗