Postural reorientation does not cause the locomotor after-effect following rotary locomotion

After a period of stepping on a rotating platform, blindfolded subjects demonstrate a tendency to unconsciously turn when stepping in place, an after-effect known as podokinetic after-rotation (PKAR). Recent studies have also reported a change in postural orientation following the adaptive period and have suggested that this is causally related to PKAR. Here, we assess changes in trunk orientation following platform adaptation and determine their relationship to PKAR. Specifically, we determine whether a reorganized standing posture causes PKAR. Ten subjects stepped on a platform rotating at 60deg/s for 10 min, with a cadence of 100 steps/min. Following adaptation, a significant PKAR response was seen, with a mean yaw rotation velocity of 6.0 ± 2.2deg/s. In addition to this dynamic after-effect, there was a significant twist of the trunk with respect to the feet when standing still (6.9 ± 4.5deg; mean ± SD), confirming the presence of a postural reorientation after-effect. However, the magnitudes of the two after-effects did not correlate (r = 0.06, p = 0.87). Furthermore, in a second experiment, a prolonged passive twist of the trunk was used to induce postural reorientation. However, in this case, PKAR was not induced. These results demonstrate that PKAR is not an automatic consequence of reorganized standing posture

DNMT and HDAC inhibitors induce cryptic transcription start sites encoded in long terminal repeats

Several mechanisms of action have been proposed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi), primarily based on candidate-gene approaches. However, less is known about their genome-wide transcriptional and epigenomic consequences. By mapping global transcription start site (TSS) and chromatin dynamics, we observed the cryptic transcription of thousands of treatment-induced non-annotated TSSs (TINATs) following DNMTi and HDACi treatment. The resulting transcripts frequently splice into protein-coding exons and encode truncated or chimeric ORFs translated into products with predicted abnormal or immunogenic functions. TINAT transcription after DNMTi treatment coincided with DNA hypomethylation and gain of classical promoter histone marks, while HDACi specifically induced a subset of TINATs in association with H2AK9ac, H3K14ac, and H3K23ac. Despite this mechanistic difference, both inhibitors convergently induced transcription from identical sites, as we found TINATs to be encoded in solitary long terminal repeats of the ERV9/LTR12 family, which are epigenetically repressed in virtually all normal cells

DNA Methylation: Biological Implications and Modulation of Its Aberrant Dysregulation

The alteration of the DNA methylation pattern is often related to the onset of diseases based on epigenetic dysregulation, primarily cancer. In this scenery the development of DNA methyltransferase inhibitors is one of the most attractive challenges for anticancer therapy. The present chapter proposes a comprehensive classification of the DNA methyltransferase inhibitors known in literature, on the basis of their natural or synthetic nature and their mechanism of action