No abstract

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

Positional cloning in maize (Zea mays) requires development of markers in the region of interest. We found that primers designed to amplify annotated insertion–deletion polymorphisms of seven base pairs or greater between B73 and Mo17 produce polymorphic markers at a 97% frequency with 49% of the products showing co-dominant fragment length polymorphisms. When the same polymorphisms are used to develop markers for B73 and W22 or Mo17 and W22 mapping populations, 22% and 31% of markers are co-dominant, respectively. There are 38,223 Indel polymorphisms that can be converted to markers providing high-density coverage throughout the maize genome. This strategy significantly increases the efficiency of marker development for fine-mapping in maize.

Parent-of-origin-effect loci have non-Mendelian inheritance in which phenotypes are determined by either the maternal or paternal allele alone. In angiosperms, parent-of-origin effects can be caused by loci required for gametophyte development or by imprinted genes needed for seed development. Few parent-of-origin-effect loci have been identified in maize (Zea mays) even though there are a large number of imprinted genes known from transcriptomics. We screened rough endosperm (rgh) mutants for parent-oforigin effects using reciprocal crosses with inbred parents. Six maternal rough endosperm (mre) and three paternal rough endosperm (pre) mutants were identified with three mre loci mapped. When inherited from the female parent, mre/+ seeds reduce grain fill with a rough, etched, or pitted endosperm surface. Pollen transmission of pre mutants results in rgh endosperm as well as embryo lethality. Eight of the mutants had significant distortion from the expected one-to-one ratio for parent-of-origin effects. Linked markers for mre1, mre2, and mre3 indicated that the mutant alleles have no bias in transmission. Histological analysis of mre1, mre2, mre3, and pre*-949 showed altered timing of starch grain accumulation and basal endosperm transfer cell layer (BETL) development. The mre1 locus delays BETL and starchy endosperm development, while mre2 and pre*-949 cause ectopic starchy endosperm differentiation. We conclude that many parent-of-origin effects in maize have incomplete penetrance of kernel phenotypes and that there is a large diversity of endosperm developmental roles for parent-of-origin-effect loci.KEYWORDS parent-of-origin effect; gametophyte; imprinting; seed; endosperm T HE maternal and paternal parents have different genetic and epigenetic contributions to angiosperm seed development. Angiosperm seeds result from the double fertilization of two multicellular gametophytes (Walbot and Evans 2003). In diploid species, gametophytes grow from the haploid products of meiosis with the male and female gametophytes following different developmental programs. The male gametophyte or pollen grain, delivers two haploid sperm cells through the pollen tube to fertilize the female gametophyte. Fertilization of the egg forms a diploid zygote, and fertilization of the two central cell nuclei forms a triploid endosperm cell. The central cell and egg cell provide the vast majority of cytoplasm for the nascent endosperm and the zygote. In addition, the central cell genome has more open chromatin, and there is substantial evidence for a dominant maternal role to initiate the coordinate development of the endosperm and embryo (Baroux and Autran 2015;Borg and Borg 2015;Del Toro-De Leon et al. 2016).Mutations in loci specific to the development of either gametophyte are expected to show non-Mendelian inheritance such as reduced transmission and maternal effect seed phenotypes. Only a few maize seed mutants have been identified with maternal effects, and most of these mutants primarily affect gametophyte development. T...

Parent-of-origin-effect loci have non-Mendelian inheritance in which phenotypes are determined by either the maternal or paternal allele alone. In angiosperms, parent-of-origin effects can be caused by loci required for gametophyte development or by imprinted genes needed for seed development. Few parent-of-origin-effect loci have been identified in maize (Zea mays) even though there are a large number of imprinted genes known from transcriptomics. We screened rough endosperm (rgh) mutants for parent-oforigin effects using reciprocal crosses with inbred parents. Six maternal rough endosperm (mre) and three paternal rough endosperm (pre) mutants were identified with three mre loci mapped. When inherited from the female parent, mre/+ seeds reduce grain fill with a rough, etched, or pitted endosperm surface. Pollen transmission of pre mutants results in rgh endosperm as well as embryo lethality. Eight of the mutants had significant distortion from the expected one-to-one ratio for parent-of-origin effects. Linked markers for mre1, mre2, and mre3 indicated that the mutant alleles have no bias in transmission. Histological analysis of mre1, mre2, mre3, and pre*-949 showed altered timing of starch grain accumulation and basal endosperm transfer cell layer (BETL) development. The mre1 locus delays BETL and starchy endosperm development, while mre2 and pre*-949 cause ectopic starchy endosperm differentiation. We conclude that many parent-of-origin effects in maize have incomplete penetrance of kernel phenotypes and that there is a large diversity of endosperm developmental roles for parent-of-origin-effect loci.KEYWORDS parent-of-origin effect; gametophyte; imprinting; seed; endosperm T HE maternal and paternal parents have different genetic and epigenetic contributions to angiosperm seed development. Angiosperm seeds result from the double fertilization of two multicellular gametophytes (Walbot and Evans 2003). In diploid species, gametophytes grow from the haploid products of meiosis with the male and female gametophytes following different developmental programs. The male gametophyte or pollen grain, delivers two haploid sperm cells through the pollen tube to fertilize the female gametophyte. Fertilization of the egg forms a diploid zygote, and fertilization of the two central cell nuclei forms a triploid endosperm cell. The central cell and egg cell provide the vast majority of cytoplasm for the nascent endosperm and the zygote. In addition, the central cell genome has more open chromatin, and there is substantial evidence for a dominant maternal role to initiate the coordinate development of the endosperm and embryo (Baroux and Autran 2015;Borg and Borg 2015;Del Toro-De Leon et al. 2016).Mutations in loci specific to the development of either gametophyte are expected to show non-Mendelian inheritance such as reduced transmission and maternal effect seed phenotypes. Only a few maize seed mutants have been identified with maternal effects, and most of these mutants primarily affect gametophyte development. T...