Biology

Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 3'UTRs (untranslated regions) upon proliferative signals and relieving microRNA-mediated repression. Owing to high proliferative indices of triple negative breast cancers (TNBCs), we hypothesized APA to cause 3'UTR length changes in this aggressive subgroup of breast cancers. Our probe-based meta-analysis approach identified 3'UTR length alterations where the significant majority was shortening events (∼70%, 113 of 165) of mostly proliferation-related transcripts in 520 TNBC patients compared with controls. Representative shortening events were further investigated for their microRNA binding potentials by computational predictions and dual-luciferase assay. In silico-predicted 3'UTR shortening events were experimentally confirmed in patient and cell line samples. To begin addressing the underlying mechanisms, we found CSTF2 (cleavage stimulation factor 2), a major regulator of 3'UTR shortening to be up-regulated in response to epidermal growth factor (EGF). EGF treatment also resulted with further shortening of the 3'UTRs. To investigate the contribution of CSTF2 and 3'UTR length alterations to the proliferative phenotype, we showed pharmacological inhibition of the EGF pathway to lead to a reduction in CSTF2 levels. Accordingly, RNAi-induced silencing of CSTF2 decreased the proliferative rate of cancer cells. Therefore, our computational and experimental approach revealed a pattern of 3'UTR length changes in TNBC patients and a potential link between APA and EGF signaling. Overall, detection of 3'UTR length alterations of various genes may help the discovery of new cancer-related genes, which may have been overlooked in conventional microarray gene expression analyses.

The archaeological documentation of the development
of sedentary farming societies in Anatolia is
not yet mirrored by a genetic understanding of the
human populations involved, in contrast to the
spread of farming in Europe . Sedentary farming
communities emerged in parts of the Fertile Crescent
during the tenth millennium and early ninth millennium
calibrated (cal) BC and had appeared in central
Anatolia by 8300 cal BC . Farming spread into
west Anatolia by the early seventh millennium cal
BC and quasi-synchronously into Europe, although
the timing and process of this movement remain unclear.
Using genome sequence data that we generated
from nine central Anatolian Neolithic individuals,
we studied the transition period from early Aceramic
(Pre-Pottery) to the later Pottery Neolithic, when
farming expanded west of the Fertile Crescent. We
find that genetic diversity in the earliest farmers
was conspicuously low, on a par with European
foraging groups. With the advent of the Pottery
Neolithic, genetic variation within societies reached
levels later found in early European farmers. Our results
confirm that the earliest Neolithic central Anatolians
belonged to the same gene pool as the first
Neolithic migrants spreading into Europe. Further,
genetic affinities between later Anatolian farmers
and fourth to third millennium BC Chalcolithic south
Europeans suggest an additional wave of Anatolian
migrants, after the initial Neolithic spread but before
the Yamnaya-related migrations. We propose that
the earliest farming societies demographically
resembled foragers and that only after regional
gene flow and rising heterogeneity did the farming
population expansions into Europe occur.

The archaeological documentation of the development of sedentary farming societies in Anatolia is not yet mirrored by a genetic understanding of the human populations involved, in contrast to the spread of farming in Europe [1–3]. Sedentary farming communities emerged in parts of the Fertile Crescent during the 10th millennium and early 9th millennium cal BC and had appeared in central Anatolia by 8300 cal BC [4]. Farming spread into west Anatolia by the early 7th millennium cal BC and quasi-synchronously into Europe, although the timing and process of this movement remain unclear. Using genome sequence data we generated from nine central Anatolian Neolithic individuals, we studied the transition period from early Aceramic (Pre-Pottery) to the later Pottery Neolithic, when farming expanded west of the Fertile Crescent. We find that genetic diversity in the earliest farmers was conspicuously low, on a par with European foraging groups. With the advent of the Pottery Neolithic, genetic variation within societies reached levels later found in early European farmers. Our results confirm that earliest Neolithic central Anatolians belonged to the same gene pool as the first Neolithic migrants spreading into Europe. Further, genetic affinities between later-coming Anatolian farmers and 3rd-4th millennium BC Chalcolithic south Europeans suggest an additional wave of Anatolian migrants, after the initial Neolithic spread, but before the Yamnaya migrations. We propose that the earliest farming societies demographically resembled foragers and only after regional gene flow and rising heterogeneity, did the farming population expansions into Europe occur.