Jarid2 Is Implicated in the Initial Xist-Induced Targeting of PRC2 to the Inactive X Chromosome

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Jarid2 regulates mouse epidermal stem cell activation and differentiation

Jarid2 is required for the genomic recruitment of the polycomb repressive complex-2 (PRC2) in embryonic stem cells. However, its specific role during late development and adult tissues remains largely uncharacterized. Here, we show that deletion of Jarid2 in mouse epidermis reduces the proliferation and potentiates the differentiation of postnatal epidermal progenitors, without affecting epidermal development. In neonatal epidermis, Jarid2 deficiency reduces H3K27 trimethylation, a chromatin repressive mark, in epidermal differentiation genes previously shown to be targets of the PRC2. However, in adult epidermis Jarid2 depletion does not affect interfollicular epidermal differentiation but results in delayed hair follicle (HF) cycling as a consequence of decreased proliferation of HF stem cells and their progeny. We conclude that Jarid2 is required for the scheduled proliferation of epidermal stem and progenitor cells necessary to maintain epidermal homeostasis.     

SHRiMP2: sensitive yet practical SHort Read Mapping

We report on a major update (version 2) of the original SHort Read Mapping Program (SHRiMP). SHRiMP2 primarily targets mapping sensitivity, and is able to achieve high accuracy at a very reasonable speed. SHRiMP2 supports both letter space and color space (AB/SOLiD) reads, enables for direct alignment of paired reads and uses parallel computation to fully utilize multi-core architectures. AVAILABILITY: SHRiMP2 executables and source code are freely available at: http://compbio.cs.toronto.edu/shrimp/.     

Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression

Jarid2/Jumonji critically regulates developmental processes including cardiovascular development. Jarid2 knock-out mice exhibit cardiac defects including hypertrabeculation with noncompaction of the ventricular wall. However, molecular mechanisms underlying Jarid2-mediated cardiac development remain unknown. To determine the cardiac lineage-specific roles of Jarid2, we generated myocardial, epicardial, cardiac neural crest, or endothelial conditional Jarid2 knock-out mice using Cre-loxP technology. Only mice with an endothelial deletion of Jarid2 recapitulate phenotypic defects observed in whole body mutants including hypertrabeculation and noncompaction of the ventricle. To identify potential targets of Jarid2, combinatorial approaches using microarray and candidate gene analyses were employed on Jarid2 knock-out embryonic hearts. Whole body or endothelial deletion of Jarid2 leads to increased endocardial Notch1 expression in the developing ventricle, resulting in increased Notch1-dependent signaling to the adjacent myocardium. Using quantitative chromatin immunoprecipitation analysis, Jarid2 was found to occupy a specific region on the endogenous Notch1 locus. We propose that failure to properly regulate Notch signaling in Jarid2 mutants likely leads to the defects in the developing ventricular chamber. The identification of Jarid2 as a potential regulator of Notch1 signaling has broad implications for many cellular processes including development, stem cell maintenance, and tumor formation.     

Regulation of mitochondrial metabolism: yet another facet in the biology of the oncoprotein Bcl-2

The Bcl-2 (Bcl is B-cell lymphocytic-leukaemia proto-oncogene) family comprises two groups of proteins with distinct functional biology in cell-fate signalling. Bcl-2 protein was the first member to be discovered and associated with drug resistance in human lymphomas. Since then a host of other proteins such as Bcl-xL, Bcl-2A1 and Mcl-1 with similar anti-apoptotic functions have been identified. In contrast, the pro-apoptotic Bcl-2 proteins contain prototypic effector proteins such as Bax and Bak, and the BH3 (Bcl-2 homology)-only proteins comprising Bak, Bid, Bim, Puma and Noxa. A complex interplay between the association of pro-apoptotic and anti-apoptotic proteins with each other determines the sensitivity of cancer cells to drug-induced apoptosis. The canonical functional of Bcl-2 in terms of apoptosis inhibition is its ability to prevent mitochondrial permeabilization via inhibiting the translocation and oligomerization of pro-apoptotic proteins such as Bax; however, more recent evidence points to a novel mechanism of the anti-apoptotic activity of Bcl-2. Overexpression of Bcl-2 increases mitochondrial oxygen consumption and in doing so generates a slight pro-oxidant intracellular milieu, which promotes genomic instability and blocks death signalling. However, in the wake of overt oxidative stress, Bcl-2 regulates cellular redox status thereby preventing excessive build-up of ROS (reactive oxygen species), which is detrimental to cells and tissues. Taken together, the canonical and non-canonical activities of Bcl-2 imply a critical involvement of this protein in the processes of tumour initiation and progression. In the present paper we review these functionally distinct outcomes of Bcl-2 expression with implications for the chemotherapeutic management of cancers.     

Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain

Jarid1c, an X-linked gene coding for a histone demethylase, plays an important role in brain development and function. Notably, JARID1C mutations cause mental retardation and increased aggression in humans. These phenotypes are consistent with the expression patterns we have identified in mouse brain where Jarid1c mRNA was detected in hippocampus, hypothalamus, and cerebellum. Jarid1c expression and associated active histone marks at its 5'end are high in P19 neurons, indicating that JARID1C demethylase plays an important role in differentiated neuronal cells. We found that XX mice expressed Jarid1c more highly than XY mice, independent of their gonadal types (testes versus ovaries). This increased expression in XX mice is consistent with Jarid1c escape from X inactivation and is not compensated by expression from the Y-linked paralogue Jarid1d, which is expressed at a very low level compared to the X paralogue in P19 cells. Our observations suggest that sex-specific expression of Jarid1c may contribute to sex differences in brain function.     

4,5-Dihydro-1H-pyrazole: an indispensable scaffold

Abstract

Pyrazoles, categorized as nitrogen-containing heterocycles, are well known for their interminable participation in the field of perpetual research and development of therapeutical active agents. As a consequence pyrazoles became an inevitable core of numerous drugs having diverse activities. The broad spectrum of activities portrayed by the pyrazoles instigated the researchers to modify the pyrazole ring as 4,5-dihydro-1H-pyrazoles commonly known as 2-pyrazolines. The present review is a concerted effort to retrace compounds covered from 2009-till date which owe diverse biological activities to the 2-pyrazoline scaffold and also condenses the retro-synthetic approaches employed for their synthesis. This endeavor culminated in revelation that inhibitory potential varied when the substituents in particular N-substituents of 2-pyrazolines were altered.     

Immunocytochemistry: an indispensable technique in routine cytology

L. Skoog and E. Tani Immunocytochemistry: an indispensable technique in routine cytology Immunocytology is today accepted as an indispensable adjunct to cytomorphology. It has led to a dramatic increase in diagnostic accuracy and also allowed the identification of markers both for prognosis and targeted therapies. Most commercially available antibodies will perform in a reproducible and reliable way provided that the cytological specimen has been prepared and fixed properly. In this review various aspects of immunocytochemistry such as preparation of cytological specimens, fixation and choice of antibodies will be discussed. The specificity of the most commonly used antibodies is summarized and staining panels for various tumours are suggested. In addition, the use of markers for targeted therapy and theranostics is discussed, as well as a brief section on the identification of infectious agents.