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Xiaoyu Hu's group reports "Negative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression"

 

    On May 8th 2020, Dr. Xiaoyu Hu’s group at the Institute for Immunology Tsinghua University published a research article entitled “Negative elongation factor complex enables macrophage inflammatory responses by controlling anti-inflammatory gene expression” in Nature Communications. This work comprehensively profiled the genome-wide RNA polymerase II pausing landscape during macrophage activation by utilizing multiple omics-technologies and revealed the role of negative elongation factor complex (NELF) during macrophage activation.

  Tight regulation of extensively activated macrophage transcriptome is critical for ensuring desirable inflammatory responses. Inspired by their previous discovery in Hes1-modulated Cxcl1 gene transcription elongation during macrophage activation (Shang et al, Nat Immunol., 2016), Hu and her colleagues further pursued the post-initiation regulatory mechanisms for macrophage gene activation, which is an under-appreciated area of research relative to the classical transcription-initiating mechanism. In this study, they comprehensively characterized promoter-proximal pausing and pausing associated regulatory modules during macrophage activation. As shown by their profiling data, transcription event in macrophage is largely regulated by post-initiation mechanism, which is evident by more than 70% of paused macrophage transcriptome in resting states and inducible transcriptional pause release in over half (71%) of LPS-induced gene during activation. Distinct from the well-established CDK9-mediated pause release by expelling the phosphorylated NELF from paused RNA polymerase II, this study revealed that LPS-induced global NELF dismissal from promoter-proximal regions acted in a CDK9-independent manner.

 

    Re-distribution of dismissed NELF in promoter proximal regions and the lack of co-localization of CDK9 with NELF are in agreement with a step-wise pause-release model for macrophage gene activation. 1) NELF dismissal lifts the inhibitory signal for pause release. 2) CDK9 in gene body subsequently potentiates permissive transcription elongation. While NELF deficiency in myeloid lineage did not result in apparent abnormalities of macrophage population and alterations of macrophage transcriptome in the resting state, NELF suppressed a select subset of immediate early genes. Moreover, hypo-inflammatory phenotype was identified in NELF depleted macrophages and NELF myeloid deficient mice under LPS-induced inflammation. Further exploration in broad NELF targeted genes showed the complexity of NELF controlled anti-inflammatory response, which is exemplified by NELF constrained activation of AP-1 coding genes, Fos and Jun, and further suppressed IL-10 production ensures the inflammatory cytokine production, such as IL-6. The NELF and CDK9 imposed step-wise post-initiation regulation that was proposed in this study renews our knowledge on classical transcriptional pause model, in which NELF mediated CDK9-independent regulation could even be generalized to other systems, such as heat shock response as recently reported (Molecular Cell 2020 Apr; 78:261). Moreover, the identified permissive function of NELF for inflammation provides the new insight to the complexity of post-initiation regulation in inflammatory response.

 

    Dr. Xiaoyu Hu from Institute for Immunology Tsinghua University and Dr. Inez Rogatsky from Weill Cornell Medicine are co-corresponding authors of this study. Ph.D. students, Li Yu and Bin Zhang, are co-first authors of this study. Other researchers from Tsinghua University, Weill Cornell Medicine, Shandong Agricultural University and George Washington University also contributed to this study. This study was supported by Ministry of Science and Technology of China, National Natural Science Foundation of China, Tsinghua-Peking Center for Life Sciences, Institute for Immunology at Tsinghua University, U.S. National Institutes of Health (NIH), U.S. Rheumatology Research Foundation Research Grant, The Hospital for Special Surgery David Rosensweig Genomics Center and U.S. Department of Defense.

 

 

Full Text Link: https://www.nature.com/articles/s41467-020-16209-5

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