Lung cancer is the leading cause of cancer-related deaths worldwide. The initiation and progression of lung cancer is the result of the interaction between permanent genetic and dynamic epigenetic alterations. DNA methylation is the best studied epigenetic mark in human cancers. Altered DNA methylation in cancer was identified in 1983. Within 30 years of this discovery, DNA methylation inhibitors are used clinically to treat a variety of cancers, highlighting the importance of the epigenetic basis of cancer. In addition, histone modifications, nucleosome remodeling, and micro RNA (miRNA)-mediated gene regulation are also fundamental to tumor genesis. Distinct chromatin alterations occur in all stages of lung cancer, including initiation, growth, and metastasis. Therefore, stage-specific epigenetic changes can be used as powerful and reliable tools for early diagnosis of lung cancer and to monitor patient prognosis. Moreover, since epigenetic changes are dynamic and reversible, chromatin modifiers are promising targets for the development of more effective therapeutic strategies against cancer. This review summarizes the chromatin alterations in lung cancer, focusing on the diagnostic and therapeutic approaches targeting epigenetic modifications that could help to reduce the high case-fatality rate of this dreadful disease.

High mobility group (HMG) proteins are the most abundant non-histone chromatin associated proteins. HMG proteins bind to DNA and nucleosome and alter the structure of chromatin locally and globally. Accessibility to DNA within chromatin is a central factor that affects DNA-dependent nuclear processes, such as transcription, replication, recombination, and repair. HMG proteins associate with different multi-protein complexes to regulate these processes by mediating accessibility to DNA. HMG proteins can be subdivided into three families: HMGA, HMGB, and HMGN. In this review, we will focus on recent advances in understanding the function of HMGA family members, specifically their role in gene transcription regulation during development and cancer.

The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; γ-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFβ1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome.

Clustered regularly interspaced short palindromic repeats (CRISPR) form the adaptive immune system in archaea and bacteria and have been modified for genome engineering in eukaryotic cells. CRISPR systems contain 2 components, a single-guide RNA, which is a short RNA composed of a 20 nucleotide sequence that targets specific sites in the genomic DNA and a scaffold necessary for its binding to the CRISPRassociated endonuclease (Cas9). Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing based therapies are poised to treat a multitude of human diseases with a promise to target previously "undruggable" proteins. As the first in-body clinical trial with CRISPR-Cas9 is embarked on, the risks associated with administering the genome editing machinery to patients become increasingly relevant. Recent studies have demonstrated an innate and adaptive cellular immune response to Cas9 in mouse models and the presence of anti-Cas9 antibodies and T-cells in human plasma. Pre-existing immunity against therapeutic Cas9 delivery could decrease its efficacy in vivo and may pose significant safety issues. This review focuses on the immunogenicity of the Cas9 protein and summarizes potential approaches to circumvent the problem of immune recognition.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal lung disease with unknown etiology and poor prognosis. IPF patients die within 2 years after diagnosis mostly due to respiratory failure. Current treatments against IPF aim to ameliorate patient symptoms and to delay disease progression. Unfortunately, therapies targeting the causes of or reverting IPF have not yet been developed. Here we show that reduced levels of miRNA lethal 7d ( MIRLET7D ) in IPF compromise epigenetic gene silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we find that hyperactive EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Remarkably, EP300 inhibition reduces fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model), and ex vivo (precision-cut lung slices, PCLS) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition.