KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state

Heterochromatin plays an essential role in the preservation of epigenetic information, the transcriptional repression of repeti- tive DNA elements and inactive genes, and the proper segregation of chromosomes during mitosis. Here we identify KDM2A, a JmjC-domain containing histone demethylase, as a heterochro- matin-associated and HP1-interacting protein that promotes HP1 localization to chromatin. We show that KDM2A is required to maintain the heterochromatic state, as determined using a candidate-based approach coupled to an in vivo epigenetic reporter system. Remarkably, a parallel and independent siRNA screen also detected a role for KDM2A in epigenetic silencing. Moreover, we demonstrate that KDM2A associates with centromeres and represses transcription of small non-coding RNAs that are encoded by the clusters of satellite repeats at the centromere. Dissecting the relationship between heterochromatin and centromeric RNA transcription is the basis of ongoing studies. We demonstrate that forced expression of these satellite RNA transcripts compromise the heterochromatic state and HP1 localization to chromatin. Finally, we show that KDM2A is required to sustain centromeric integ- rity and genomic stability, particularly during mitosis. Since the disruption of epigenetic control mechanisms contributes to cellular transformation, these results, together with the low levels of KDM2A found in prostate carcinomas, suggest a role for KDM2A in cancer development

ДЕФОРМАЦИИ В ЦЕНТРАЛЬНО-АМЕРИКАНСКОЙ ЗОНЕ СУБДУКЦИИ ПО ДАННЫМ МЕХАНИЗМОВ ОЧАГОВ ЗЕМЛЕТРЯСЕНИЙ И ИХ ОСОБЕННОСТИ В РАЙОНЕ ЗЕМЛЕТРЯСЕНИЯ ЧЬЯПАС, МЕКСИКА, 2017 г., МW=8.2

Seismotectonic deformations in the Middle America Trench and their features in the area of preparation of the Chiapas earthquake, МW=8.2, 08 September 2017, were determined using the data on 2244 focal mechanisms of earthquakes for the period of 1977–2017. The distribution of seismicity with depth was studied in detail. The decrease in the depth of the Benioff zone in the north-western subduction segments and the increase in the south-eastern segments is associated with the age of the subducting parts of the Cocos plate and the angle of their immersion. The latter mechanism can also explain the presence of earthquakes with normal focal mechanism on the oceanic uplift in the south-eastern segments of the subduction zone and their absence in the north-western ones. In general, the typical character of subduction deformations has a number of features in the Middle America Trench. The predominance of shortening by horizontal components and elongation by vertical ones at depths up to 35 km is replaced by the transitional type with mosaic distribution of deformations of different signs in the depth range of 36–70 km. Even lower, in the depth range of 70–105 km, the type of deformation changes to the opposite with respect to the upper horizon. The Chiapas earthquake occurred on the border of regions with different types of deformation, which indicates softening of the block’s medium to the west of the hypocenter and its hardening to the east. Such a state of the lithospheric medium may indicate the presence of a deformation shadow zone in the Chiapas earthquake preparation area.Сейсмотектонические деформации в Центрально-Американской зоне субдукции и их особенности в районе подготовки землетрясения Чьяпас, Мw=8.2, 8.09.2017 г., определены по данным о 2244 механизмах очагов землетрясений за период 1977–2017 гг. Детально изучено распределение сейсмичности с глубиной. Уменьшение глубины распространения зоны Беньофа в северо-западных сегментах субдукции и увеличение в юго-восточных связываются с возрастом субдуцирующих частей плиты Кокос и углом их погружения. Последний механизм может объяснять также факт наличия землетрясений со сбросовыми подвижками на океаническом поднятии Центрально-Американской зоны субдукции в юго-восточных сегментах и их отсутствие в северо-западных. В целом характерный для зон субдукции тип деформирования среды имеет в Центрально- Американской зоне субдукции ряд особенностей. Преобладание на глубинах до 35 км укорочения по горизонтальным компонентам и удлинения по вертикальной сменяется в интервале глубин 36–70 км переходным типом с мозаичным распределением деформаций разного знака и еще ниже, в диапазоне глубин 70–105 км, характеризуется противоположным по отношению к верхнему горизонту типом деформаций. Землетрясение Чьяпас произошло на границе областей с разным типом деформирования, что свидетельствует о наличии условий разупрочнения блочной среды к западу от гипоцентра и ее стеснения к востоку. Подобный характер состояния среды может указывать на наличие зоны деформационной тени в области подготовки землетрясения Чьяпас

Epigenetic inactivation of the splicing RNA-binding protein CELF2 in human breast cancer.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadHuman tumors show altered patterns of protein isoforms that can be related to the dysregulation of messenger RNA alternative splicing also observed in transformed cells. Although somatic mutations in core spliceosome components and their associated factors have been described in some cases, almost nothing is known about the contribution of distorted epigenetic patterns to aberrant splicing. Herein, we show that the splicing RNA-binding protein CELF2 is targeted by promoter hypermethylation-associated transcriptional silencing in human cancer. Focusing on the context of breast cancer, we also demonstrate that CELF2 restoration has growth-inhibitory effects and that its epigenetic loss induces an aberrant downstream pattern of alternative splicing, affecting key genes in breast cancer biology such as the autophagy factor ULK1 and the apoptotic protein CARD10. Furthermore, the presence of CELF2 hypermethylation in the clinical setting is associated with shorter overall survival of the breast cancer patients carrying this epigenetic lesion.Health Department PERIS-project of the Catalan Government (Generalitat de Catalunya) AGAUR of the Catalan Government (Generalitat de Catalunya) Instituto de Salud Carlos III Ministerio de Economia y Competitividad (MINECO) European Union (EU) Foundation CELLEX La Caixa Foundatio

Clinicopathological comparison of triple negative breast cancers with non‑triple negative breast cancers in a hospital in North India

Introduction: Breast cancer is the second most common cancer worldwide (1.3 million cases, 10.9%) and ranks 5th as cause of death from cancer overall (458,000 cases, 6.1%). Triple‑negative breast cancer (TNBC) is a subtype of breast cancer with characteristic biological and pathological features. Among the subgroups of breast cancer, triple negative cancer is particularly feared because it is associated with poor outcome. However, clinical data on TNBC in Asian population are limited. The present study was aimed to find the prevalence of TNBCs and to compare various clinicopathological features of TNBC with non TNBC patients in our population.Materials and Methods: Clinical and pathological data of 180 breast cancer patients who visited our department from January 2009 to December 2013 were analyzed. Statistical analysis was done using the Chi‑square test and Mann–Whitney U‑test.Results: Of 180 cases, 62 (34.4%) had TNBC. Data analysis revealed significant difference in mean age, mean tumor size, tumor grade between TNBC and non‑TNBC patients. Axillary lymph node metastasis and lymphovascular involvement were also more in TNBC patients however this was not statistically significant. Extranodal spread was recorded more in non‑TNBC patients as compared to TNBC patients, but the results were statistically insignificant.Conclusion: Triple negative breast cancer represented 34.4% which is higher than the range normally reported in the literature. TNBC are associated with younger age, large tumor size, high‑grade tumors, and a higher rate of axillary lymph node metastasis.Key words: Basal subtype, estrogen receptor, hormone receptors, human epidermal growth factor receptor‑2/neu, progesterone receptor, triple negativ

μ-Calpain is essential for postmortem proteolysis of muscle proteins

The objective of this investigation was to test the hypothesis that μ-calpain is largely responsible for postmortem proteolysis of muscle proteins. To accomplish this objective, we compared proteolysis of known muscle proteins in muscles of wild type and μ-calpain knockout mice during postmortem storage. Knockout mice (n = 6) were killed along with control mice (n = 6). Hind limbs were removed and stored at 4°C. Muscles were dissected at 0, 1, and 3d postmortem and subsequently analyzed for degradation of nebulin, dystrophin, metavinculin, vinculin, desmin, and tropo-nin T. In a separate experiment, hind limb muscles from knockout (n = 4) and control mice (n = 4) were analyzed at 0, 1, and 3 d postmortem using casein zy-mography to confirm that μ-calpain activity was knocked out in muscle and to determine whether or not μ-calpain is activated in murine postmortem muscle. Cumulatively, the results of the first experiment indicated that postmortem proteolysis was largely inhibited in μ-calpain knockout mice. The results of the second experiment established the absence of μ-calpain in the muscle tissue of knockout mice and confirmed the results of an earlier study that μ-calpain is active in postmortem murine muscle. The results of the current study show that even in a species in which μ-calpain is activated to some extent postmortem, μ-calpain is largely responsible for postmortem proteolysis. This observation excludes a major role for any of the other members of the calpain family or any other proteolytic system in postmortem proteolysis of muscle proteins. Therefore, understanding the regulation of μ-calpain in postmortem muscle should be the focus of further research on postmortem proteolysis and tenderization of meat

DEFORMATIONS IN THE MIDDLE AMERICA TRENCH ACCORDING TO EARTHQUAKE FOCAL MECHANISMS AND THEIR FEATURES IN THE AREA OF THE 2017 МW 8.2 CHIAPAS EARTHQUAKE, MEXICO

Seismotectonic deformations in the Middle America Trench and their features in the area of preparation of the Chiapas earthquake, МW=8.2, 08 September 2017, were determined using the data on 2244 focal mechanisms of earthquakes for the period of 1977–2017. The distribution of seismicity with depth was studied in detail. The decrease in the depth of the Benioff zone in the north-western subduction segments and the increase in the south-eastern segments is associated with the age of the subducting parts of the Cocos plate and the angle of their immersion. The latter mechanism can also explain the presence of earthquakes with normal focal mechanism on the oceanic uplift in the south-eastern segments of the subduction zone and their absence in the north-western ones. In general, the typical character of subduction deformations has a number of features in the Middle America Trench. The predominance of shortening by horizontal components and elongation by vertical ones at depths up to 35 km is replaced by the transitional type with mosaic distribution of deformations of different signs in the depth range of 36–70 km. Even lower, in the depth range of 70–105 km, the type of deformation changes to the opposite with respect to the upper horizon. The Chiapas earthquake occurred on the border of regions with different types of deformation, which indicates softening of the block’s medium to the west of the hypocenter and its hardening to the east. Such a state of the lithospheric medium may indicate the presence of a deformation shadow zone in the Chiapas earthquake preparation area