LSH mediates gene repression through macroH2A deposition

The human Immunodeficiency Centromeric Instability Facial Anomalies (ICF) 4 syndrome is a severe disease with increased mortality caused by mutation in the LSH gene. Although LSH belongs to a family of chromatin remodeling proteins, it remains unknown how LSH mediates its function on chromatin in vivo. Here, we use chemical-induced proximity to rapidly recruit LSH to an engineered locus and find that LSH specifically induces macroH2A1.2 and macroH2A2 deposition in an ATP-dependent manner. Tethering of LSH induces transcriptional repression and silencing is dependent on macroH2A deposition. Loss of LSH decreases macroH2A enrichment at repeat sequences and results in transcriptional reactivation. Likewise, reduction of macroH2A by siRNA interference mimicks transcriptional reactivation. ChIP-seq analysis confirmed that LSH is a major regulator of genome-wide macroH2A distribution. Tethering of ICF4 mutations fails to induce macroH2A deposition and ICF4 patient cells display reduced macroH2A deposition and transcriptional reactivation supporting a pathogenic role for altered marcoH2A deposition. We propose that LSH is a major chromatin modulator of the histone variant macroH2A and that its ability to insert marcoH2A into chromatin and transcriptionally silence is disturbed in the ICF4 syndrome

Daily (In)Activities of Nursing Home Residents in Their Wards: An Observation Study

Objectives: Research shows that nursing home residents are largely inactive. This inactivity negatively influences physical fitness, and participation in daily activities is known to have a positive influence on physical function and quality of life. Existing research does not provide sufficient insight into the daily activities in which nursing home residents participate. This insight is needed to develop future interventions so as to encourage nursing home residents to participate in daily activities and, thereby, decrease inactivity. The purpose of this study was to obtain insight into daily (in) activities of psychogeriatric and somatic nursing home residents during the day and their body positions during these (in) activities. Design: Cross-sectional observation study. Setting: Nursing homes in the Netherlands (19 psychogeriatric and 11 somatic wards). Participants: Participants were 723 home residents in 7 nursing homes. Measurements: Observations were conducted using a self-developed observation list. Residents were observed in their wards during 5 random observation times between 7:00 AM and 11:00 PM, in which the daily activity and position of the resident during this activity were scored. Percentages of activities and positions were calculated for each observation time. Results: In total, 3282 observations (91% of the intended 3615 observations) were conducted. Nursing home residents of both psychogeriatric and somatic wards were mainly observed partaking in inactivities, such as sleeping, doing nothing, and watching TV (range: 45%-77% of the 5 observation times). Furthermore, residents were engaged in activities of daily living (ADLs) (range: 15%-38%) that mainly comprised activities related to mobility (range: 10%-19%) and eating and drinking (range: 2%-17%). Engagement of residents in instrumental ADLs (IADLs) was rarely observed (up to 3%). Residents were largely observed in a lying or sitting position (range: 89%-92%). Conclusion: Most of the psychogeriatric and somatic nursing home residents spend their day inactive in a lying or sitting position in the ward. To encourage nursing home residents in daily activities in the wards, interventions are needed that (1) focus on increasing ADLs and IADLs, and (2) encourage standing and walking