The bldC developmental locus of Streptomyces coelicolor encodes a member of a family of small DNA-binding proteins related to the DNA-binding domains of the MerR family.

The bldC locus, required for formation of aerial hyphae in Streptomyces coelicolor, was localized by map-based cloning to the overlap between cosmids D17 and D25 of a minimal ordered library. Subcloning and sequencing showed that bldC encodes a member of a previously unrecognized family of small (58- to 78-residue) DNA-binding proteins, related to the DNA-binding domains of the MerR family of transcriptional activators. BldC family members are found in a wide range of gram-positive and gram-negative bacteria. Constructed {Delta}bldC mutants were defective in differentiation and antibiotic production. They failed to form an aerial mycelium on minimal medium and showed severe delays in aerial mycelium formation on rich medium. In addition, they failed to produce the polyketide antibiotic actinorhodin, and bldC was shown to be required for normal and sustained transcription of the pathway-specific activator gene actII-orf4. Although {Delta}bldC mutants produced the tripyrrole antibiotic undecylprodigiosin, transcripts of the pathway-specific activator gene (redD) were reduced to almost undetectable levels after 48 h in the bldC mutant, in contrast to the bldC+ parent strain in which redD transcription continued during aerial mycelium formation and sporulation. This suggests that bldC may be required for maintenance of redD transcription during differentiation. bldC is expressed from a single promoter. S1 nuclease protection assays and immunoblotting showed that bldC is constitutively expressed and that transcription of bldC does not depend on any of the other known bld genes. The bldC18 mutation that originally defined the locus causes a Y49C substitution that results in instability of the protein

A connection between stress and development in the multicelular prokaryote Streptomyces coelicolor

Morphological changes leading to aerial mycelium formation and sporulation in the mycelial bacterium Streptomyces coelicolor rely on establishing distinct patterns of gene expression in separate regions of the colony. sH was identified previously as one of three paralogous sigma factors associated with stress responses in S. coelicolor. Here, we show that sigH and the upstream gene prsH (encoding a putative antisigma factor of sH) form an operon transcribed from two developmentally regulated promoters, sigHp1 and sigHp2. While sigHp1 activity is confined to the early phase of growth, transcription of sigHp2 is dramatically induced at the time of aerial hyphae formation. Localization of sigHp2 activity using a transcriptional fusion to the green fluorescent protein reporter gene (sigHp2–egfp) showed that sigHp2 transcription is spatially restricted to sporulating aerial hyphae in wild-type S. coelicolor. However, analysis of mutants unable to form aerial hyphae (bld mutants) showed that sigHp2 transcription and sH protein levels are dramatically upregulated in a bldD mutant, and that the sigHp2–egfp fusion was expressed ectopically in the substrate mycelium in the bldD background. Finally, a protein possessing sigHp2 promoter-binding activity was purified to homogeneity from crude mycelial extracts of S. coelicolor and shown to be BldD. The BldD binding site in the sigHp2 promoter was defined by DNase I footprinting. These data show that expression of sH is subject to temporal and spatial regulation during colony development, that this tissue-specific regulation is mediated directly by the developmental transcription factor BldD and suggest that stress and developmental programmes may be intimately connected in Streptomyces morphogenesis

Shared heritability and functional enrichment across six solid cancers

Correction: Nature Communications 10 (2019): art. 4386 DOI: 10.1038/s41467-019-12095-8Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.Peer reviewe

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis

Intermediate Filaments Supporting Cell Shape and Growth in Bacteria

For years intermediate filaments (IF), belonging to the third class of filamentous cytoskeletal proteins alongside microtubules and actin filaments, were thought to be exclusive to metazoan cells. Structurally these eukaryote IFs are very well defined, consisting of globular head and tail domains, which flank the central rod-domain. This central domain is dominated by an α-helical secondary structure predisposed to form the characteristic coiled-coil, parallel homo-dimer. These elementary dimers can further associate, both laterally and longitudinally, generating a variety of filament-networks built from filaments in the range of 10 nm in diameter. The general role of these filaments with their characteristic mechano-elastic properties both in the cytoplasm and in the nucleus of eukaryote cells is to provide mechanical strength and a scaffold supporting diverse shapes and cellular functions. Since 2003, after the first bacterial IF-like protein, crescentin was identified, it has been evident that bacteria also employ filamentous networks, other than those built from bacterial tubulin or actin homologues, in order to support their cell shape, growth and, in some cases, division. Intriguingly, compared to their eukaryote counterparts, the group of bacterial IF-like proteins shows much wider structural diversity. The sizes of both the head and tail domains are markedly reduced and there is great variation in the length of the central rod-domain. Furthermore, bacterial rod-domains often lack the sub-domain organisation of eukaryote IFs that is the defining feature of the IF-family. However, the fascinating display of filamentous assemblies, including rope, striated cables and hexagonal laces together with the conditions required for their formation both in vitro and in vivo strongly resemble that of eukaryote IFs suggesting that these bacterial proteins are deservedly classified as part of the IF-family and that the current definition should be relaxed slightly to allow their inclusion. The lack of extensive head and tail domains may well make the bacterial proteins more amenable for structural characterisation, which will be essential for establishing the mechanism for their association into filaments. What is more, the well-developed tools for bacterial manipulations provide an excellent opportunity of studying the bacterial systems with the prospect of making significant progress in our understanding of the general underlying principles of intermediate filament assemblies

Initiation of aerial mycelium formation in Streptomyces

In the past two years, the isolation of extracellular factors involved in the initiation of aerial mycelium formation, the identification of metabolic defects in certain developmental mutants, and the characterisation of three further bid genes and several γ-butyrolactone receptor genes have led to new ideas about the mechanisms that initiate aerial mycelium formation in Streptomyces. The emerging picture suggests the integration of numerous signals from both inside and outside the cell

Cloning and characterization of gentamicin-resistance genes from Micromonospora purpurea and Micromonospora rosea

Aminoglycoside-resistance genes (grm) were cloned from a gentamicin producer Micromonospora purpurea and a sisomicin producer Micromonospora rosea. The nucleotide (nt) sequences of both genes were determined and the similarity between them was very high (90.4% identity). In either case, the transcription start point was localised to about 11 nt upstream from the likely translation start codons of grm, which is expressed as a polycistronic transcript. In studies to be reported elsewhere, it has been established that the M. purpurea grm gene encodes a ribosomal RNA methyltransferase. Here, we confirmed that the similarity of the two genes exists not only at the structural but also at the functional level