The majority of eukaryotic genes produce multiple mRNA isoforms by using alternative poly(A) sites in a process called alternative polyadenylation (APA). APA is a dynamic process that is highly regulated in development and in response to extrinsic or intrinsic stimuli. Mis-regulation of APA has been linked to a wide variety of diseases, including cancer, neurological and immunological disorders. Since the first example of APA was described 40 years ago, the regulatory mechanisms of APA have been actively investigated. Conventionally, research in this area has focused primarily on the roles of regulatory cis-elements and trans-acting RNA-binding proteins. Recent studies, however, have revealed important functions for epigenetic mechanisms, including DNA and histone modifications and higher-order chromatin structures, in APA regulation. Here we will discuss these recent findings and their implications for our understanding of the crosstalk between epigenetics and mRNA 3'-end processing.
BACKGROUND: Robotic therapy can improve upper limb function in
hemiparesis. Excitatory transcranial direct current stimulation (tDCS) can prime
brain motor circuits before therapy.OBJECTIVE: We tested safety and efficacy of tDCS plus robotic therapy in
an adult with unilateral spastic cerebral palsy (USCP).METHODS: In each of 36 sessions, anodal tDCS (2 mA,
20 min) was applied over the motor map of the affected hand. Immediately after
tDCS, the participant completed robotic therapy, using the shoulder, elbow, and wrist
(MIT Manus). The participant sat in a padded chair with affected arm abducted,
forearm supported, and hand grasping the robot handle. The participant controlled the
robot arm with his affected arm to move a cursor from the center of a circle to each
of eight targets (960 movements). Motor function was tested before, after, and six
months after therapy with the Wolf Motor Function Test (WMFT) and Fugl-Meyer
(FM).RESULTS: Reaching accuracy on the robot task improved significantly
after therapy. The WMFT and FM improved clinically meaningful amounts after therapy.
The motor map of the affected hand expanded after therapy. Improvements were
maintained six months after therapy.CONCLUSIONS: Combined tDCS and robotics safely improved upper limb
function in an adult with USCP.
JTE-607 is a small molecule compound with anti-inflammation and anti-cancer activities. Upon entering the cell, it is hydrolyzed to Compound 2, which directly binds to and inhibits CPSF73, the endonuclease for the cleavage step in pre-mRNA 3' processing. Although CPSF73 is universally required for mRNA 3' end formation, we have unexpectedly found that Compound 2-mediated inhibition of pre-mRNA 3' processing is sequence-specific and that the sequences flanking the cleavage site (CS) are a major determinant for drug sensitivity. By using massively parallel in vitro assays, we have measured the Compound 2 sensitivities of over 260,000 sequence variants and identified key sequence features that determine drug sensitivity. A machine learning model trained on these data can predict the impact of JTE-607 on poly(A) site (PAS) selection and transcription termination genome-wide. We propose a biochemical model in which CPSF73 and other mRNA 3' processing factors bind to RNA of the CS region in a sequence-specific manner and the affinity of such interaction determines the Compound 2 sensitivity of a PAS. As the Compound 2-resistant CS sequences, characterized by U/A-rich motifs, are prevalent in PASs from yeast to human, the CS region sequence may have more fundamental functions beyond determining drug resistance. Together, our study not only characterized the mechanism of action of a compound with clinical implications, but also revealed a previously unknown and evolutionarily conserved sequence-specificity of the mRNA 3' processing machinery.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.