Fibroblasts constitute the major mesenchymal cell type in the connective tissue and their functions are remarkably diverse: here, by characterising lineages of mouse skin fibroblasts, it is shown that distinct subpopulations contribute to skin development and repair during injury. Fibroblasts are unremarkable looking cells found in most tissues in the body, where they are mainly concerned with making the collagen that supports other cell types. The cells all look much the same yet are functionally diverse, prompting the question, is there just one cell type responding differently to different stimuli, or do individual cells specialize? A transplantation and lineage tracing study in mice now shows that skin connective tissue arises from two distinct fibroblast lineages that also contribute differentially to skin development and repair after injury. One cell type forms the lower dermis and the other the upper dermis. The latter lineage is required for hair follicle production. In wounded adult skin, the initial wave of dermal repair is mediated by the 'lower' lineage, which may explain the absence of hair follicles in newly closed wounds. The authors develop a comprehensive lineage tree for all fibroblast-derived cell types in mouse dermis, including smooth muscle cells and adipocytes. Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibres of the extracellular matrix (ECM)1. Even within a single tissue, fibroblasts exhibit considerable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing in mice, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle, which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesize the bulk of the fibrillar ECM, and the preadipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialization. Epidermal β-catenin activation stimulates the expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles2,3,4. They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.

A number of large noncoding RNAs (ncRNAs) epigenetically silence genes through unknown mechanisms. The Air ncRNA is imprinted—monoallelically expressed from the paternal allele. Air is required for allele-specific silencing of the cis-linked Slc22a3, Slc22a2 , and Igf2r genes in mouse placenta. We show that Air interacts with the Slc22a3 promoter chromatin and the H3K9 histone methyltransferase G9a in placenta. Air accumulates at the Slc22a3 promoter in correlation with localized H3K9 methylation and transcriptional repression. Genetic ablation of G9a results in nonimprinted, biallelic transcription of Slc22a3 . Truncated Air fails to accumulate at the Slc22a3 promoter, which results in reduced G9a recruitment and biallelic transcription. Our results suggest that Air , and potentially other large ncRNAs, target repressive histone-modifying activities through molecular interaction with specific chromatin domains to epigenetically silence transcription.

The nutritional sins of the mother…: Prenatal exposures of a mother can affect the health of her offspring, but how? Radford et al. found that the male progeny of undernourished pregnant mice had altered DNA chemistry in their sperm. In addition, the offspring displayed compromised metabolic health. The specific affected genes not only lost DNA methylation but also lacked the normal sperm DNA packaging factors (protamines) and instead were enriched in nucleosomes. Thus, when subjected to a suboptimal prenatal environment, offspring feel the effects of the maternal assault. Science , this issue p. 10.1126/science.1255903