ultivated cotton is one of the most economically important crop plants in the world. The allotetraploid Upland cotton, G. hirsutum (n = 2x = 26, (AD) 1), currently dominates the world's cotton commerce 1,2. Hybridization between the Old World A-genome progenitor and a New World D-genome ancestor, followed by chromosome doubling, formed the allopolyploid cotton ~1−2 million years ago (Ma) 3,4. Uncertainty regarding the actual A-genome donor of the widely cultivated allotetraploid cotton G. hirsutum has persisted 5-13. A 1 (n = x = 13) and A 2 (n = x = 13), commonly known as African and Asiatic cotton, respectively, are the only two extant diploid A-genome species in the world 14. Stephens first proposed in Nature, using genetic and morphological evidence, that A 2 was the A-genome donor of present-day allopolyploid cottons 6. Gerstel argued via cytogenetic studies that A 1 was more closely related to the A-genome in the allopolyploids than A 2 (ref. 8). Despite recent efforts to sequence the cotton genomes, including Gossypium raimondii (D 5) 15,16 , A 2 (refs. 17,18), (AD) 1 (refs. 10,19-21) and Gossypium barbadense 10,21 ((AD) 2 , a much less cultivated tetraploid cotton), the origin history of the A-genome donor for the tetraploid (AD) 1-genome 5,11,13 and the extent of divergence between the A-genomes remain elusive 22,23. Abundant studies support a Gossypium species resembling D 5 as the D-genome donor 13 , but currently there is no solid evidence to suggest that the actual A-genome donor of tetraploid cottons is either A 2 (refs. 6,7,10,19) or A 1 (refs. 8,9,11-13) as has been suggested. In this study, we assembled A 1 variety africanum for the first time and reassembled high-quality A 2 cultivar Shixiya1 and (AD) 1 genetic standard Texas Marker-1 (TM-1) genomes on the basis of PacBio long reads, paired-end sequencing and high-throughput chromosome conformation capture (Hi-C) technologies. Upon assembling and updating cotton genomes, we revealed the origin of cotton A-genomes, the occurrence of several transposable element (TE) bursts and the genetic divergence of diploid A-genomes worldwide. Also, we identified abundant structural variations (SVs) that have affected the expression of neighboring genes and help explain phenotypic differences among the cotton species. Results Sequencing and assembly of three high-quality cotton genomes. Here we sequenced the A 1-genome var. africanum for the first time by generating ~225-gigabase (Gb) PacBio single-molecule real-time (SMRT) long reads (the N50 (minimum length to cover 50% of the total length) of these reads was 13 kilobases (kb)) with 138-fold genome coverage. We generated an assembly that captured 1,556 megabases (Mb) of genome sequences, consisting of 1,781 contigs with the N50 of these contigs reaching up to 1,915 kb (Table 1). The initial assemblies were then corrected by using highly accurate Illumina paired-end reads (Supplementary Table 1). Finally, 95.69% of total contigs spanning 1,489 Mb were categorized and ordered into 13 chromosome-scale scaffold...

A conserved guanine-rich sequence could be a new target for anti–hepatitis C virus drug development.

Upon recognition of antigen, B cells undertake a bifurcated response in which some cells rapidly differentiate into plasmablasts while others undergo affinity maturation in germinal centers (GCs). Here we identified a double-negative feedback loop between the transcription factors IRF4 and IRF8 that regulated the initial developmental bifurcation of activated B cells as well as the GC response. IRF8 dampened signaling via the B cell antigen receptor (BCR), facilitated antigen-specific interaction with helper T cells, and promoted antibody affinity maturation while antagonizing IRF4-driven differentiation of plasmablasts. Genomic analysis revealed concentration-dependent actions of IRF4 and IRF8 in regulating distinct gene-expression programs. Stochastic modeling suggested that the double-negative feedback was sufficient to initiate bifurcation of the B cell developmental trajectories.

Langerhans cells (LC) can prime tolerogenic as well as immunogenic responses in skin, but the genomic states and transcription factors (TF) regulating these context-specific responses are unclear. Bulk and single-cell transcriptional profiling demonstrates that human migratory LCs are robustly programmed for MHC-I and MHC-II antigen presentation. Chromatin analysis reveals enrichment of ETS-IRF and AP1-IRF composite regulatory elements in antigen-presentation genes, coinciding with expression of the TFs, PU.1, IRF4 and BATF3 but not IRF8. Migration of LCs from the epidermis is accompanied by upregulation of IRF4, antigen processing components and co-stimulatory molecules. TNF stimulation augments LC cross-presentation while attenuating IRF4 expression. CRISPR-mediated editing reveals IRF4 to positively regulate the LC activation programme, but repress NF2EL2 and NF-kB pathway genes that promote responsiveness to oxidative stress and inflammatory cytokines. Thus, IRF4-dependent genomic programming of human migratory LCs appears to enable LC maturation while attenuating excessive inflammatory and immunogenic responses in the epidermis.

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