Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

Fast parallel algorithms for short-range molecular dynamics

Tremendous amount of RNA sequencing data have been produced by large consortium projects such as TCGA and GTEx, creating new opportunities for data mining and deeper understanding of gene functions. While certain existing web servers are valuable and widely used, many expression analysis functions needed by experimental biologists are still not adequately addressed by these tools. We introduce GEPIA (Gene Expression Profiling Interactive Analysis), a web-based tool to deliver fast and customizable functionalities based on TCGA and GTEx data. GEPIA provides key interactive and customizable functions including differential expression analysis, profiling plotting, correlation analysis, patient survival analysis, similar gene detection and dimensionality reduction analysis. The comprehensive expression analyses with simple clicking through GEPIA greatly facilitate data mining in wide research areas, scientific discussion and the therapeutic discovery process. GEPIA fills in the gap between cancer genomics big data and the delivery of integrated information to end users, thus helping unleash the value of the current data resources. GEPIA is available at http://gepia.cancer-pku.cn/.

GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses.

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

http://bionmr.ustc.edu.cn/courses/nature09504.pdf

Selective inhibition of BET bromodomains.

Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes

Unrestrained activation of receptor tyrosine kinase (RTK) pathways drives tumorigenesis through the persistent activation of critical signaling pathways, including the Ras-ERK axis. This aberrant signaling is unleashed by mutations in signaling effectors such as Ras, as well as through disruption of feedback control by regulatory proteins such as the Sprouty family. Mutations in epigenetic regulators also commonly occur during cancer progression, modulating chromatin architecture and gene expression. While unrestrained signaling and epigenetic deregulation are root causes of tumorigenesis, the relationship between aberrant RTK signaling and chromatin modifications at cis-regulatory elements remains to be fully elucidated. We establish linkage between these processes by examining the effects of oncogenic HRasG12V or loss of feedback regulation by Sprouty on global changes in gene expression and enhancer-associated chromatin modifications. Using RNA-sequencing and ChIP-sequencing, we demonstrate that aberrant RTK signaling unleashed by oncogenic HRasG12V or Sprouty gene deletion disrupts gene expression programs and remodels histone modifications associated with active enhancers, including histone 3 lysine 27 acetylation (H3K27ac). Abolishing persistent Ras-Erk signaling through chemical inhibition of MEK activity reverses the aberrant transcriptional program and H3K27ac remodeling at deregulated enhancers. While both lesions disrupt the Ras-Erk axis, the specific target genes and enhancers modulated upon HRasG12V-transformation or Sprouty deletion are largely distinct. Specifically, oncogenic HRasG12V significantly elevates the expression and H3K27ac levels near key target genes encoding the transcription factor Gata4 and the kinase Prkcb. Gata4 is necessary for the HRasG12V expression program and coordinates H3K27ac marking at enhancers of deregulated target genes. We further show that HRasG12V-driven cells are sensitive to chemical inhibition of Prkcb, which reduces the viability and clonogenicity of HRasG12V-transformed cells. These oncogenic effects upon HRasG12V-transformation are also reduced by chemical inhibition of the chromatin regulators BET bromodomain proteins and p300/CBP, which recognize and deposit H3K27ac, respectively. Taken together, our data support a model in which dynamic reprogramming of the cellular enhancer landscape is a key effect of oncogenic RTK signaling. Furthermore, our study shows that identification of enhancers regulated by oncogenic Ras yields insight into targeting key epigenetic regulators and downstream factors that promote Ras-driven malignancies. Citation Format: Behnam Nabet, Pilib O Broin, Jaime Reyes, Kevin Shieh, Charles Y. Lin, Christine M. Will, Relja Popovic, Teresa Ezponda, James E. Bradner, Aaron A. Golden, Jonathan D. Licht. Deregulation of the Ras-Erk signaling axis modulates the enhancer landscape. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2209. doi:10.1158/1538-7445.AM2015-2209

Abstract 2209: Deregulation of the Ras-Erk signaling axis modulates the enhancer landscape


 Small-cell lung cancer (SCLC) is a highly aggressive malignancy, with a 5-year survival rate below 5%. In contrast to non-small cell lung cancer, in which treatment advancements have shown much success, there has not been significant progress in the development of new therapies for SCLC over the last 40 years. Thus, an urgent need exists to identify new and effective pharmacological interventions for these patients.
 Recent advancements in the understanding of the pathology of the disease has shown that SCLC tumorigenesis and evolution is governed by increased expression of neuroendocrine-associated and other proto-oncogenic transcription factors such as ASCL1, NEUROD1, and MYC. Thus, targeting transcription may be an effective therapeutic strategy. Cyclin-dependent kinase 9 (CDK9) is a serine-threonine kinase that is involved in transcriptional elongation through the phosphorylation of the RNA polymerase II. Additionally, CDK9 interacts with transcription factors such as MYC to promote activation of target genes. Inhibition of CDK9 results in disrupted transcriptional networks and inhibition of cancer cell proliferation and survival, making CDK9 an attractive target for the treatment of SCLC. We have developed a highly selective and orally bioavailable inhibitor of CDK9, KB-0742. Here we present the evaluation of KB-0742 activity in preclinical models of SCLC.
 Using the Broad PRISM platform, we evaluated the sensitivity of 24 SCLC cell lines. We observed a correlation between MYC copy number amplification and sensitivity with amplified lines having smaller AUC values than non-amplified lines (Mann-Whitney-Wilcoxon; P>0.05). We observed a similar trend of lower IC50 values with increasing levels of MYC expression in a separate cell-line screen that included 5 SCLC lines (Pearson’s correlation; P=0.71).
 We then evaluated KB-0742 activity in a panel of 6 patient-derived organoid (PDO) SCLC models with different treatment histories and compared to 4 standard-of-care (SOC) compounds. KB-0742 was more active than the SOC compounds, with maximum inhibition rates of over 90% for 5 of the 6 models. In a separate study of 4 treatment-naïve PDO models, KB-0742 was active in 3 different transcription factor-driven subtypes of SCLC, and the response correlated significantly with c-MYC and MYCL expression. Lastly, we used 4 patient-derived xenograft (PDX) models to evaluate KB-0742 activity in vivo. The tumor growth inhibition (TGI) rate ranged from 54% to 92%, with tumor regressions observed in 2 of the 4 models, and 1 model showed greater TGI with KB-0742 than the SOC.
 These data support the development of KB-0742 as a potential treatment for SCLC. Patients with relapsed or refractory solid tumors or non-Hodgkin lymphoma are currently being enrolled in a phase 1/2 clinical trial of KB-0742 (NCT04718675) with an expansion arm for SCLC being planned after the recommended phase 2 dose is identified.
 Citation Format: Melinda A. Day, Douglas C. Saffran, Tressa Hood, Nikolaus Obholzer, Akanksha Pandey, Charles Y. Lin, Pavan Kumar, Jorge DiMartino. CDK9 inhibitor KB-0742 is active in preclinical models of small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2565.

Abstract 2565: CDK9 inhibitor KB-0742 is active in preclinical models of small-cell lung cancer

Cancer cells have the extraordinary evolutionary potential to adapt and acquire resistance to most conventional and targeted therapies. In a new study, Lin et al., develop a systematic approach to identify combination therapies that produce cancer traps, in which evading the first drug makes the cancer vulnerable to the second.

Springing an evolutionary trap on cancer.

The disclosure provides adenosine deaminases that are capable of deaminating adenosine in DNA to treat Hutchinson-Gilford progeria syndrome (HOPS). The disclosure also provides fusion proteins, guide RNAs and compositions comprising a Cas9 ( e.g ., a Cas9 nickase) domain and adenosine deaminases that deaminate adenosine in DNA, for example in a LMNA gene. In some embodiments, adenosine deaminases provided herein are used to correct a C1824T mutation in LMNA . In some embodiments, the methods and compositions provided herein are used to treat Hutchinson-Gilford progeria syndrome (HGPS).

Base editing for treating hutchinson-gilford progeria syndrome

/pdf/cdk7-controls-e2f-and-myc-driven-proliferative-and-metabolic-fjj2234d.pdf

Charles Y. Lin

Papers

Abstract 2209: Deregulation of the Ras-Erk signaling axis modulates the enhancer landscape

Abstract 2565: CDK9 inhibitor KB-0742 is active in preclinical models of small-cell lung cancer

Springing an evolutionary trap on cancer.

Base editing for treating hutchinson-gilford progeria syndrome

CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma