The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are preferentially targeted to distal lineage specific enhancers and interact with p300 to modulate histone H3 lysine 27 acetylation. We identify a greater requirement for SWI/SNF at typical enhancers than at most super-enhancers and at enhancers in untranscribed regions than in transcribed regions. Our data further demonstrate that SWI/SNF-dependent distal enhancers are essential for controlling expression of genes linked to developmental processes. Our findings thus establish SWI/SNF complexes as regulators of the enhancer landscape and provide insight into the roles of SWI/SNF in cellular fate control.

Targeting EZH2 in cancer.

Recent genomic studies have resulted in an emerging understanding of the role of chromatin regulators in the development of cancer. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex, is recurrently mutated in several forms of cancer and is highly expressed in numerous others. Notably, both gain-of-function and loss-of-function mutations occur in cancers but are associated with distinct cancer types. Here we review the spectrum of EZH2-associated mutations, discuss the mechanisms underlying EZH2 function, and synthesize a unifying perspective that the promotion of cancer arises from disruption of the role of EZH2 as a master regulator of transcription. We further discuss EZH2 inhibitors that are now showing early signs of promise in clinical trials and also additional strategies to combat roles of EZH2 in cancer.

SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2.

Human cancer genome sequencing has recently revealed that genes that encode subunits of SWI/SNF chromatin remodeling complexes are frequently mutated across a wide variety of cancers, and several subunits of the complex have been shown to have bona fide tumor suppressor activity. However, whether mutations in SWI/SNF subunits result in shared dependencies is unknown. Here we show that EZH2, a catalytic subunit of the polycomb repressive complex 2 (PRC2), is essential in all tested cancer cell lines and xenografts harboring mutations of the SWI/SNF subunits ARID1A, PBRM1, and SMARCA4, which are several of the most frequently mutated SWI/SNF subunits in human cancer, but that co-occurrence of a Ras pathway mutation is correlated with abrogation of this dependence. Notably, we demonstrate that SWI/SNF-mutant cancer cells are primarily dependent on a non-catalytic role of EZH2 in the stabilization of the PRC2 complex, and that they are only partially dependent on EZH2 histone methyltransferase activity. These results not only reveal a shared dependency of cancers with genetic alterations in SWI/SNF subunits, but also suggest that EZH2 enzymatic inhibitors now in clinical development may not fully suppress the oncogenic activity of EZH2.

Mechanisms by which SMARCB1 loss drives rhabdoid tumor growth.

SMARCB1 (INI1/SNF5/BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in the large majority of rhabdoid tumors, and germline heterozygous SMARCB1 mutations form the basis for rhabdoid predisposition syndrome. Mouse models validated Smarcb1 as a bona fide tumor suppressor, as Smarcb1 inactivation in mice results in 100% of the animals rapidly developing cancer. SMARCB1 was the first subunit of the SWI/SNF complex found mutated in cancer. More recently, at least seven other genes encoding SWI/SNF subunits have been identified as recurrently mutated in cancer. Collectively, 20% of all human cancers contain a SWI/SNF mutation. Consequently, investigation of the mechanisms by which SMARCB1 mutation causes cancer has relevance not only for rhabdoid tumors, but also potentially for the wide variety of SWI/SNF mutant cancers. Here we discuss normal functions of SMARCB1 and the SWI/SNF complex as well as mechanistic and potentially therapeutic insights that have emerged.

CHD7 in charge of neurogenesis.

In this issue of Cell Stem Cell, Feng et al. (2013) report that the gene mutated in human CHARGE syndrome, ATP-dependent chromatin remodeling factor CHD7, contributes to the control of neurogenesis. The authors also report that exercise ameliorates these defects and suggest it as an intervention worthy of study in CHARGE syndrome.

Sleep and fatigue symptoms in women before and 6 weeks after hysterectomy.

OBJECTIVE: To compare sleep and fatigue experiences of women before hysterectomy and at 3 and 6 weeks after surgery, to compare symptoms by type of surgical procedure, and to examine the biopsychosocial contextual factors related to symptoms. DESIGN: A descriptive repeated measures study assessed sleep and fatigue using questionnaires and objective wrist actigraphy monitoring for sleep. SETTING: Data were collected in women's homes at least 2 days before surgery, and at 3 and 6 weeks postoperatively. PARTICIPANTS: A convenience sample of 25 women scheduled for hysterectomy. RESULTS: There was significantly higher self-reported sleep disturbance 3 weeks after surgery compared with baseline. Women who had vaginal hysterectomy continued to experience sleep disturbance and fatigue 6 weeks after surgery, while those who had abdominal hysterectomy reported better sleep and less fatigue at 6 weeks compared with baseline. The number of awakenings recorded with actigraphy increased postoperatively for both groups, and younger women experienced more wake time during the night than older women. Level of education was positively related to preoperative fatigue severity. CONCLUSIONS: Findings suggested poor sleep and fatigue during the postoperative period should be evaluated in light of women's ages, level of education, and type of surgical procedure.

Clinical competence among senior nursing students after their preceptorship experiences.

The senior nursing preceptorship is the culminating clinical experience in the baccalaureate nursing program and assists students in the application of their nursing knowledge and skills. Students' success in getting their first job may also depend on this clinical preceptorship. How well they learn to practice their nursing skills before graduating may determine the success of their transition from being a student nurse to becoming a staff nurse. This descriptive study explored the perceptions of senior baccalaureate nursing students about their clinical preceptorship program. Perceptions were examined in relation to (a) the degree of students' interaction with the preceptor and (b) the degree of their perceptions of competence in using the nursing process. Data were collected from 102 senior nursing students with the use of a 52-item survey questionnaire that included opinion and competence statements. The results suggest that the clinical preceptorship program increased the overall perceived competence of 91 of the 102 nursing students. With a greater amount of preceptor interaction, there was a greater degree of perceived competence in nursing skills among the students. Ninety-six percent of the students rated their relationship with their preceptor as important to very important. The results also identified strong and weak areas of perceived clinical skills in the students. These results will help in facilitating future senior nursing preceptorship placements.

Baccalaureate nursing students' experiences of anxiety producing situations in the clinical setting.

The purpose of this study was to identify the clinical experiences of nursing students that were anxiety provoking and examine the relationship between the level of trait anxiety and the clinical experience that produced anxiety in nursing students. A descriptive correlational design collected data from 61 nursing students in their last semester of the baccalaureate nursing program using survey questionnaires that captured demographic data and included the Trait Anxiety Scale and the Clinical Experience Assessment form. Analyses of data indicate that 36% of the students experienced a moderate level of anxiety. Clinical experiences related to arriving late, being observed by instructors, responding to initial experiences, having a fear of making mistakes, and talking to physicians were the most anxiety producing for these students. A significantly positive relationship (r = .40, p < .05) was found between the trait anxiety and clinical experience that was anxiety producing. A higher level of perceived anxiety accompanied the following clinical experiences; being observed by instructors (F = 3.44, p = .04), doing beforehand in-hospital preparation (F = 4.46, p < .02), asking questions of faculty (F = 4.38, p < .02), being evaluated by faculty (F = 3.37, p < .04), and reporting to team leader (F = 3.60, p < .05). The most anxiety producing clinical experiences in nursing students before graduation are evaluated with descriptive data. Results would provide useful insights for faculty and senior nursing students involved in clinical practice, and have implications for education, further research, and clinical support.