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Angiogenesis underlies development, physiology and pathogenesis of cancer, eye and cardiovascular diseases. Inhibiting aberrant angiogenesis using anti-angiogenic therapy (AAT) has been successful in the clinical treatment of cancer and eye diseases. However, resistance to AAT inevitably occurs and its molecular basis remains poorly understood. Here, we uncover molecular modifiers of the blood endothelial cell (EC) response to a widely used AAT bevacizumab by performing a pooled genetic screen using three-dimensional microcarrier-based cell culture and CRISPR-Cas9. Functional inhibition of the epigenetic reader BET family of proteins BRD2/3/4 shows unexpected mitigating effects on EC survival and/or proliferation upon VEGFA blockade. Moreover, transcriptomic and pathway analyses reveal an interaction between epigenetic regulation and anti-angiogenesis, which may affect chromosomal structure and activity in ECs via the cell cycle regulator CDC25B phosphatase. Collectively, our findings provide insight into epigenetic regulation of the EC response to VEGFA blockade and may facilitate development of quality biomarkers and strategies for overcoming resistance to AAT.

B lymphoid development is initiated by the differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating mature B cells. This highly regulated process generates clonal immunological diversity via recombination of immunoglobulin V, D and J gene segments. While several transcription factors that control B cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene (Erg) is essential for early B lymphoid differentiation. Erg initiates a transcriptional network involving the B cell lineage defining genes, Ebf1 and Pax5, which directly promotes expression of key genes involved in V(D)J recombination and formation of the B cell receptor. Complementation of Erg deficiency with a productively rearranged immunoglobulin gene rescued B lineage development, demonstrating that Erg is an essential and stage-specific regulator of the gene regulatory network controlling B lymphopoiesis.Copyright © 2020, The Author(s).

The fast economic development of the People’s Republic of China has created an increasing demand for usable land, resulting in large-scale land reclamations along the coastal zone. One of these regions is Tongzhou Bay (Jiangsu coast), a region characterized by large intertidal mudflats and deep tidal channels with potential for the development of agri-aquaculture and the construction of a deep-sea port. However, these intertidal mudflats also provide vital ecosystem services and support many wildlife species, including several endangered migratory shorebirds within the East Asian–Australasian Flyway. With increasing realization of the importance of maintaining such ecological values, a more integrated coastal development strategy is needed. This study aims to develop a sustainable integrated design for the Tongzhou Bay port, following a “Building with Nature” approach. We use a morphodynamic model to compute habitat suitability for two shorebird species (Great Knot Calidris tenuirostris and Bar-tailed Godwit Limosa lapponica). Several port configurations were developed on the basis of three design criteria: (1) create area for future port development, whilst (2) preserving existing high-value ecotopes for shorebirds and (3) enhance the natural accretion rate of such ecotopes. Simulation results showed a clear difference in siltation patterns, preservation and enhancement of preferred ecotopes. This work therefore demonstrates the potential and importance of morphological and habitat suitability modelling when designing large-scale reclamations and port constructions, especially in dynamic areas such as Tongzhou Bay.

China's continuous and rapid economic growth has led to the reclamation of large sections of the intertidal mud coast in combination with port construction, such as that of the proposed Tongzhou Bay port on the Jiangsu coast. These reclamations threaten the local ecosystem services. An ecotope distribution map was created and a hydrodynamic numerical model of Tongzhou Bay was set up to quantify the impacts of reclamation on the ecosystem. Based on the field data and model results, several abiotic features were classified into 11 ecotopes and visualized in an ecotope map of the Tongzhou Bay ecosystem. Validation with spatial distributions of two threatened shorebird species (bar-tailed godwit and great knot) showed confirmation with the mid-range and low-range littoral zones (inundated from 40% to 100% of a tidal cycle), indicating the importance of the areas with these conditions to these populations. Overlaying the ecotope map with recent and proposed land reclamation schemes revealed a loss of ecotopes, composed of the high-range (42%), mid-range (48%), and low-range (38%) littoral habitats, corresponding to a 44%–45% loss of the most important ecotopes for bar-tailed godwit and great knot (mid-range and low-range littoral zones). These results confirm the applicability of the novel ecotope assessment approach in practice.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.

B lymphoid development is initiated by the differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating mature B cells. This highly regulated process generates clonal immunological diversity via recombination of immunoglobulin V, D and J gene segments. While several transcription factors that control B cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene (Erg) is essential for early B lymphoid differentiation. Erg initiates a transcriptional network involving the B cell lineage defining genes, Ebf1 and Pax5, which directly promotes expression of key genes involved in V(D)J recombination and formation of the B cell receptor. Complementation of Erg deficiency with a productively rearranged immunoglobulin gene rescued B lineage development, demonstrating that Erg is an essential and stage-specific regulator of the gene regulatory network controlling B lymphopoiesis.