Master transcription factors interact with DNA to establish cell-type identity and to regulate gene expression in mammalian cells1,2. The genome-wide map of these transcription factor binding sites has been termed the cistrome3. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13, co-localized with the reprogrammed AR sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium towards transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.

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SUMMARYFour UK strains of three different serotypes were found to differ by only 2-3% of their S1 amino acids. The S1 sequences were also very similar to those of three Dutch isolates (D207, D274 and D3896), the greatest difference between two of the seven isolates being 4.4%. The few amino acid differences between the seven isolates were located largely between residues 19-122 and 251-347 of the mature S1 subunit.The seven isolates could be differentiated using 16 monoclonal antibodies in an enzymelinked immunosorbent assay. Some virus neutralizing (VN) antibody-inducing epitopes were common to all seven isolates even though the strains had been differentiated into three serotypes by polyclonal sera. The results indicate that the most antigenic of the VN antibody-inducing epitopes are formed by very few amino acids and that these occur in the first and third quarters of the S1 subunit. We suggest that serology-based epizootiological studies of IBV should, therefore, be augmented by the inclusion of nucleic acid sequencing and/or monoclonal antibody analysis.

The history, current situation and control measures for infectious bronchitis virus (IBV) variants are reviewed. A large number of IBV variants exist worldwide; some being unique to a particular area, others having a more general distribution. The possible reasons why some strains spread readily over major parts of the world, whereas other strains stay more localized are discussed. The advantages and disadvantages of strain classification by protectotyping, serotyping and genotyping are discussed in relation to in vivo protection. The different vaccination strategies are also considered.

The regime of administering the infectious bronchitis (IB) Ma5 vaccine (Massachusetts serotype) at 1 day old and the heterologous 4/91 vaccine at 2 weeks of age, was shown to be highly effective in protecting the respiratory tract of speci® ed pathogen free chickens. Protection, as measured by assessing ciliary activity of the tracheal epithelium following challenge, was excellent against challenge at 5 weeks of age with IB strains of many serotypes, isolated from disease outbreaks in different parts of the world. This vaccination protocol was more effective than revaccination with a vaccine of the same serotype as the ® rst vaccine. Furthermore, signi® cantly better protection was seen when the Ma5 vaccine was given before, rather than at the same time as or following, the 4/91 vaccine.It is suggested that the use of these two IB vaccines will frequently broaden the protection possible against challenge with IB isolates of many different serotypes, without the need to develop a new IB vaccine to combat each new IB serotype that emerges.

Estrogen receptor a (ERa) expression in breast cancer is predictive of response to endocrine therapy; however, resistance is common in ERa-positive tumors that overexpress the growth factor receptor ERBB2. Even in the absence of estrogen, ERa can be activated by growth factors, including the epidermal growth factor (EGF). EGF induces a transcriptional program distinct from estrogen; however, the mechanism of the stimulus-specific response is unknown. Here we show that the EGF-induced ERa genomic targets, its cistromes, are distinct from those induced by estrogen in a process dependent on the transcription factor AP-1. The EGF-induced ERa cistrome specifically regulates genes found overexpressed in ERBB2-positive human breast cancers. This provides a potential molecular explanation for the endocrine therapy resistance seen in ERa-positive breast cancers that overexpress ERBB2. These results suggest a central role for ERa in hormone-refractory breast tumors dependent on growth factor pathway activation and favors the development of therapeutic strategies completely antagonizing ERa, as opposed to blocking its estrogen responsiveness alone.[Keywords: ERBB2; breast cancer; cistrome; estrogen receptor; growth factors; transcription] Supplemental material is available at http://www.genesdev.org.

The notion that the S1 subunit of the spike glycoprotein (S) of infectious bronchitis virus (IBV) is the major inducer of protective immunity has been examined. Groups of 10 1-day-old chicks were vaccinated with isolate UK/6/82 and challenged in-tranasally 3 or 6 weeks later with strains whose S1 protein differed from that of UK/6/82 to different extents: NL/D207/79, UK/142/86 and UK/167/84 (2%), UK/123/82 (4%), UK/918/67 (19%), USA/M41/41 and Portugal/322/82 (20%; both of the Massachusetts serotype), and NL/D1466/79 (49%). Four days after challenge tracheas were removed and observed for ciliary activity. Overall, the degree of cross-protection induced by UK/6/82 diminished as the similarity of the S1 proteins diminished, although in only two cases was the protection induced statistically less (P< 0.10) against the heterologous isolates than against the homologous strain. Even when a group as a whole was poorly protected against heterologous challenge, some individual chicks, including some challenged with D1466, exhibited high protection of the trachea. Conversely, in groups where protection was high overall, a few individuals were poorly protected. The results broadly support the view that differences in the sequence of the S1 protein do contribute to the ability of an IBV strain to break through the immunity induced by another strain. However, they also indicate that some conserved sequences in S1 and/or epitopes in the other, less variable, proteins also contribute to immunity. Moreover, individual chicks can differ greatly in their response to vaccination with IBV, a factor which should not be overlooked.

A study has been made of the use of chicken tracheal organ cultures for the isolation and assay of avian infectious bronchitis (AIB) virus from both naturally and experimentally infected chickens. Six strains of AIB virus were investigated, 3 of which had been isolated from natural outbreaks of disease. Two of the virus isolations from the outbreaks of AIB were made directly into tracheal organ cultures without passage in embryonated eggs. Organ cultures prepared from 20-day-old embryos were used since they were found to be somewhat more sensitive in virus assay than those derived from chickens of up to 31 days of age. Ciliostasis, which was used as the marker of infectivity, was complete by 3 days after inoculation with each strain of virus examined. Virus could be isolated from both respiratory and non-respiratory tissue in tracheal organ cultures and these cultures were found to be at least as sensitive as 9-day-old embryonated eggs in detecting AIB virus either in pathological material or in serial dilutions. When virus was assayed in both systems, the titres were very similar. It is considered, therefore, that chicken embryo tracheal organ cultures offer a reliable alternative system to embryonated eggs for studying AIB virus.