Biology subjects

Chiba, T.

Publications and source records attributed to Chiba, T..

21 records · Page 2Linked to original sources

bioRxiv2019

Morphogenesis of giant telomeric nuclear bodies in cancer cells with alternative lengthening of telomeres

Some cancer cells lengthen their telomeres by alternative lengthening of telomeres (ALT); these are referred to as ALT cancer cells and do not express telomerase. The ALT mechanism involves the elongation of telomeric DNA repeats by homologous recombination. In interphase nuclei of ALT cancer cells, giant telomeres can be specifically observed by fluorescence in situ hybridization (FISH) to detect telomeric repeats, and they are co-localized with promyelocytic-leukemia nuclear-bodies (PML-NBs). However, it how large telomeres specific to ALT and how they form a structural relation with PML-NBs. We refer to giant telomeres specific to interphase ALT cancer cells giant-telomeric nuclear-bodies (GT-NBs). To quantitatively define GT-NBs, we performed telomeric FISH of both interphase nuclei and metaphase chromosomes and analyzed telomere sizes by integrated FISH signals. The distributions of telomere sizes in telomerase-positive cells were similar in interphase nuclei and chromosomes. However, the distribution of telomere sizes in ALT cancer cells differed between interphase nuclei and chromosomes. Giant telomeres that were larger than those at chromosomal ends were only observed in interphase nuclei of ALT cancer cells. Accordingly, GT-NBs could be quantitatively defined as larger than the maximum size of telomeres at chromosomal ends. Furthermore, ALT cancer cells demonstrated fewer telomeric signals in interphase nuclei than in chromosomes. These findings indicate that GT-NBs could be formed by the aggregation of two or more telomeres at chromosomal ends. Furthermore, super-resolution microscopy showed that GT-NBs contain one or two PML-NBs. GT-NBs are considered aggregates of telomeres and could contain multiple sites of homologous recombination accompanied by PML-NBs. These findings may contribute to the development of therapeutic approaches for ALT cancer. (251 words)

pathology↗

bioRxiv2019

The lncRNA NEAT1_1 is dispensable for normal tissue homeostasis and cancer cell growth

NEAT1 is one of the most studied lncRNAs, in part because its silencing in mice causes defects in mammary gland development and corpus luteum formation, and protects them from skin cancer development. Moreover, depleting NEAT1 in established cancer cell lines reduces growth and sensitizes cells to DNA damaging agents. However, NEAT1 produces two isoforms and because the short isoform, NEAT1_1, completely overlaps the 5 part of the long NEAT1_2 isoform, the respective contributions of each of the isoforms to these phenotypes has remained unclear. Whereas NEAT1_1 is highly expressed in most tissues, NEAT1_2 is the central architectural component of paraspeckles, which are nuclear bodies that assemble in specific tissues and cells exposed to various forms of stress. Using dual RNA-FISH to detect both NEAT1_1 outside of paraspeckles and NEAT1_2/NEAT1 inside this nuclear body, we report herein that NEAT1_1 levels are dynamically regulated during the cell cycle and targeted for degradation by the nuclear RNA exosome. Unexpectedly, however, cancer cells engineered to lack NEAT1_1, but not NEAT1_2, do not exhibit cell cycle defects. Moreover, Neat1_1-specific knockout mice do not exhibit the phenotypes observed in Neat1-deficient mice. We propose that NEAT1 functions are mainly, if not exclusively, attributable to NEAT1_2 and, by extension, to paraspeckles.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/574582_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (54K):\norg.highwire.dtl.DTLVardef@1ceaf78org.highwire.dtl.DTLVardef@6203b2org.highwire.dtl.DTLVardef@e0d5c9org.highwire.dtl.DTLVardef@f37f92_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

molecular biology↗

bioRxiv2017

Towards an Unconscious Neurotherapy for Common Fears

Can evolutionarily hardwired fear responses, e.g. for spiders and snakes, be reprogramed unconsciously in the human brain? Currently, exposure therapy is amongst the most effective treatments for anxiety disorders1, but this intervention is subjectively aversive to patients, and rates of premature attrition from treatment have been reported to be as high as 70%2. Here we introduce a novel method to bypass the subjective unpleasantness in conscious exposure, by directly pairing monetary reward with unconscious occurrences of decoded representations of naturally feared objects in the brain. The typical way to identify multivoxel functional magnetic resonance imaging (fMRI) representations for feared objects involves repeated presentations of the relevant images explicitly to subjects. However, for our potential treatment method to be effective in actual clinical settings, we need to decode fear representations without triggering excessively aversive reactions which may cause patients to dropout from treatments prematurely. Here we overcome this challenge by capitalizing on recent advancements in fMRI decoding techniques: We employed a method called hyperalignment3,4 to infer the relevant representations of feared objects for a designated participant based on data from other surrogate participants. This way the procedure completely bypasses the need for the conscious encountering of feared objects. We demonstrate that our method can lead to reliable reductions in physiological fear responses measured by skin conductance as well as amygdala hemodynamic activity. Not only do these results raise the intriguing possibility that naturally occurring fear can be re-programmed outside of conscious awareness, importantly they also created the rare opportunity for a psychological intervention of this nature to be tested rigorously in a double-blind placebo-controlled fashion. This may pave the way for a novel treatment method, combining the appealing rationale and proven efficacy of conventional psychotherapy with the rigor and leverage of clinical neuroscience.

neuroscience↗