Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation

CELNETANALYZER: HIGH-PERFORMANCE JAVA PACKAGE FOR THE TOPOLOGICAL ANALYSIS OF CELLULAR NETWORKS

Summary: A simple-to-use Java-based software package CelNetAnalyzer was developed. CelNetAnalyzer is managed through a graphical user interface and it returns a comprehensive list of the topological indices including compositional complexity, degree and neighbourhood, clustering, distance, centrality and heterogeneity indices as well as simple cycles and Shannon information entropy of undirected networks. Comparative studies have shown that due to parallelization and use of enhanced and newly developed algorithms, CelNetAnalyzer calculates these parameters significantly faster than competitors. Availability and Implementation: CelNetAnalyzer is an open-source project and free distributed for non-commercial use. Software package, source code, test network and the results of the topological analysis can be downloaded from website of the Department of Genetics at Belarusian State University (http://bio.bsu.by/genetics/grinev_software.html). Supplementary information: Supplementary data are available at Journal of Bioinformatics and Genomics onlin

Complex-dependent histone acetyltransferase activity of KAT8 determines its role in transcription and cellular homeostasis

Acetylation of lysine 16 on histone H4 (H4K16ac) is catalyzed by histone acetyltransferase KAT8 and can prevent chromatin compaction in vitro. Although extensively studied in Drosophila, the functions of H4K16ac and two KAT8-containing protein complexes (NSL and MSL) are not well understood in mammals. Here, we demonstrate a surprising complex-dependent activity of KAT8: it catalyzes H4K5ac and H4K8ac as part of the NSL complex, whereas it catalyzes the bulk of H4K16ac as part of the MSL complex. Furthermore, we show that MSL complex proteins and H4K16ac are not required for cell proliferation and chromatin accessibility, whereas the NSL complex is essential for cell survival, as it stimulates transcription initiation at the promoters of housekeeping genes. In summary, we show that KAT8 switches catalytic activity and function depending on its associated proteins and that, when in the NSL complex, it catalyzes H4K5ac and H4K8ac required for the expression of essential genes

Epigenetic regulator genes direct lineage switching in MLL/AF4 leukaemia

The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukaemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukaemia resulting in poor clinical outcomes due to resistance towards chemo- and immuno-therapies. Here we show that the myeloid relapses share oncogene fusion breakpoints with their matched lymphoid presentations and can originate from varying differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programmes, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex, NuRD. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4-positive cell models indicating that lineage switching in MLL/AF4 leukaemia is driven and maintained by disrupted epigenetic regulation