T-cell identity and epigenetic memory

T-cell development endows cells with a flexible range of effector differentiation options, superimposed on a stable core of lineage-specific gene expression that is maintained while access to alternative hematopoietic lineages is permanently renounced. This combination of features could be explained by environmentally responsive transcription factor mobilization overlaying an epigenetically stabilized base gene expression state. For example, "poising" of promoters could offer preferential access to T-cell genes, while repressive histone modifications and DNA methylation of non-T regulatory genes could be responsible for keeping non-T developmental options closed. Here, we critically review the evidence for the actual deployment of epigenetic marking to support the stable aspects of T-cell identity. Much of epigenetic marking is dynamically maintained or subject to rapid modification by local action of transcription factors. Repressive histone marks are used in gene-specific ways that do not fit a simple, developmental lineage-exclusion hierarchy. We argue that epigenetic analysis may achieve its greatest impact for illuminating regulatory biology when it is used to locate cis-regulatory elements by catching them in the act of mediating regulatory change

Resolving the prevalence of somatic transposition in Drosophila

Somatic transposition in mammals and insects could increase cellular diversity and neural mobilization has been implicated in age-dependent decline. To understand the impact of transposition in somatic cells it is essential to reliably measure the frequency and map locations of new insertions. Here we identified thousands of putative somatic transposon insertions in neurons from individual Drosophila melanogaster using whole-genome sequencing. However, the number of de novo insertions did not correlate with transposon expression or fly age. Analysing our data with exons as "immobile genetic elements" revealed a similar frequency of unexpected exon translocations. A new sequencing strategy that recovers transposon : chromosome junction information revealed most putative de novo transposon and exon insertions likely result from unavoidable chimeric artefacts. Reanalysis of other published data suggests similar artefacts are often mistaken for genuine somatic transposition. We conclude that somatic transposition is less prevalent in Drosophila than previously envisaged

Transposon expression in the Drosophila brain is driven by neighboring genes and diversifies the neural transcriptome

Somatic transposon expression in neural tissue is commonly considered as a measure of mobilization and has therefore been linked to neuropathology and organismal individuality. We combined genome sequencing data with single-cell mRNA sequencing of the same inbred fly strain to map transposon expression in the Drosophila midbrain and found that transposon expression patterns are highly stereotyped. Every detected transposon is resident in at least one cellular gene with a matching expression pattern. Bulk RNA sequencing from fly heads of the same strain revealed that coexpression is a physical link in the form of abundant chimeric transposon-gene mRNAs. We identified 264 genes where transposons introduce cryptic splice sites into the nascent transcript and thereby significantly expand the neural transcript repertoire. Some genes exclusively produce chimeric mRNAs with transposon sequence; on average, 11.6% of the mRNAs produced from a given gene are chimeric. Conversely, most transposon-containing transcripts are chimeric, which suggests that somatic expression of these transposons is largely driven by cellular genes. We propose that chimeric mRNAs produced by alternative splicing into polymorphic transposons, rather than transposon mobilization, may contribute to functional differences between individual cells and animals

Resolving the prevalence of somatic transposition in Drosophila

Somatic transposition in mammals and insects could increase cellular diversity and neural mobilization has been implicated in age-dependent decline. To understand the impact of transposition in somatic cells it is essential to reliably measure the frequency and map locations of new insertions. Here we identified thousands of putative somatic transposon insertions in neurons from individual Drosophila melanogaster using whole-genome sequencing. However, the number of de novo insertions did not correlate with transposon expression or fly age. Analysing our data with exons as "immobile genetic elements" revealed a similar frequency of unexpected exon translocations. A new sequencing strategy that recovers transposon : chromosome junction information revealed most putative de novo transposon and exon insertions likely result from unavoidable chimeric artefacts. Reanalysis of other published data suggests similar artefacts are often mistaken for genuine somatic transposition. We conclude that somatic transposition is less prevalent in Drosophila than previously envisaged

High resolution anatomical mapping confirms the absence of a magnetic sense system in the rostral upper beak of pigeons.

The cells that are responsible for detecting magnetic fields in animals remain undiscovered. Previous studies have proposed that pigeons employ a magnetic sense system that consists of six bilateral patches of magnetite containing dendrites located in the rostral subepidermis of the upper beak. We have challenged this hypothesis arguing that clusters of iron-rich cells in this region are macrophages, not magnetosensitive neurons. Here we present additional data in support of this conclusion. We have undertaken high resolution anatomical mapping of iron-rich cells in the rostral upper beak of pigeons, excluding the possibility that a conserved six-loci magnetic sense system exists. In addition we have extended our immunohistochemical studies to a second cohort of pigeons, confirming that iron rich cells in the upper beak are positive for MHCII and CD44, which are expressed by macrophages. We argue that it is important to critically assess conclusions that have been made in the past, while keeping an open mind as the search for the magnetoreceptor continues

A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.

To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6del23–29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23–29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in ∼64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6