Results of a Prospective Non-Interventional Post-Authorization Safety Study of Idelalisib in Germany.

Background: In pivotal studies, idelalisib demonstrated remarkable efficacy and manageable tolerability in patients with chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This prospective, multicenter, non-interventional post-authorization study assessed the characteristics, clinical management, and outcome of CLL and FL patients receiving idelalisib in routine clinical practice in Germany.

Patients: Observational study in CLL and FL patients treated with idelalisib between September 2015 and December 2020.

Quiescence-induced LncRNAs trigger H4K20 trimethylation and transcriptional silencing.

A complex network of regulatory pathways links transcription to cell growth and proliferation. Here we show that cellular quiescence alters chromatin structure by promoting trimethylation of histone H4 at lysine 20 (H4K20me3). In contrast to pericentric or telomeric regions, recruitment of the H4K20 methyltransferase Suv4-20h2 to rRNA genes and IAP elements requires neither trimethylation of H3K9 nor interaction with HP1 proteins but depends on long noncoding RNAs (lncRNAs) that interact with Suv4-20h2.

Dynamic changes of the epigenetic landscape during cellular differentiation.

Epigenetic mechanisms are crucial to stabilize cell type-specific gene-expression programs. However, during differentiation, these programs need to be modified - a complex process that requires dynamic but tightly controlled rearrangements in the epigenetic landscape. During recent years, the major epigenetic machineries for gene activation and repression have been extensively characterized.

Suv4-20h2 mediates chromatin compaction and is important for cohesin recruitment to heterochromatin.

Cohesin plays an important role in chromatid cohesion and has additional functions in higher-order chromatin organization and in transcriptional regulation. The binding of cohesin to euchromatic regions is largely mediated by CTCF or the mediator complex. However, it is currently unknown how cohesin is recruited to pericentric heterochromatin in mammalian cells.

CENP-C facilitates the recruitment of M18BP1 to centromeric chromatin.

Centromeres are important structural constituents of chromosomes that ensure proper chromosome segregation during mitosis by providing defined sites for kinetochore attachment. In higher eukaryotes, centromeres have no specific DNA sequence and thus, they are rather determined through epigenetic mechanisms. A fundamental process in centromere establishment is the incorporation of the histone variant CENP-A into centromeric chromatin, which provides a binding platform for the other centromeric proteins.

Heterochromatin dysregulation in human diseases.

Heterochromatin is a repressive chromatin state that is characterized by densely packed DNA and low transcriptional activity. Heterochromatin-induced gene silencing is important for mediating developmental transitions, and in addition, it has more global functions in ensuring chromosome segregation and genomic integrity. Here we discuss how altered heterochromatic states can impair normal gene expression patterns, leading to the development of different diseases.

A yeast two-hybrid system reconstituting substrate recognition of the von Hippel-Lindau tumor suppressor protein.

The von Hippel-Lindau tumor suppressor protein (pVHL) is inactivated in the hereditary cancer syndrome von Hippel-Lindau disease and in the majority of sporadic renal carcinomas. pVHL is the substrate-binding subunit of the CBC(VHL) ubiquitin ligase complex that negatively regulates cell growth by promoting the degradation of hypoxia-inducible transcription factor subunits (HIF1/2alpha). Proteomics-based identification of novel pVHL substrates is hampered by their short half-life and low abundancy in mammalian cells.