Long non-coding RNAs (lncRNAs) are receiving increasing attention as biomarkers for cancer diagnosis and therapy. Although there are many computational methods to identify cancer lncRNAs, they do not comprehensively integrate multi-omics features for predictions or systematically evaluate the contribution of each omics to the multifaceted landscape of cancer lncRNAs. In this study, an algorithm, POCALI, is developed to identify cancer lncRNAs by integrating 44 omics features across six categories. The contributions of different omics are explored to identifying cancer lncRNAs and, more specifically, how each feature contributes to a single prediction. The model is evaluated and benchmarked POCALI with existing methods. Finally, the cancer phenotype and genomics characteristics of the predicted novel cancer lncRNAs are validated. POCALI identifies secondary structure and gene expression-related features as strong predictors of cancer lncRNAs, and epigenomic features as moderate predictors. POCALI performed better than other methods, especially in terms of sensitivity, and predicted more candidates. Novel POCALI-predicted cancer lncRNAs have strong relationships with cancer phenotypes, similar to known cancer lncRNAs. Overall, this study facilitates the identification of previously undetected cancer lncRNAs and the comprehensive exploration of the multifaceted feature contributions to cancer lncRNA prediction.

The truncating mutations of LMNA are the major causes of cardiomyopathy. Here we studied 3 mouse models that carry germline, cardiomyocyte-specific, or genetic mosaic Lmna truncating mutations. Whereas the germline mutant manifested cardiac maturation defects, cardiomyocyte-specific mutation triggered pathological hypertrophy. In genetic mosaic analysis, no morphological defects were observed. Three adeno-associated virus (AAV) vectors were applied to addback lamin-A in a ubiquitous, cardiomyocyte-specific, or cardiomyocyte-excluded manner. Strikingly, only ubiquitous and cardiomyocyte-excluded AAV vectors mitigated the cardiac defects. Therefore, Lmna regulates cardiac morphology and function via a non-cell-autonomous mechanism. Noncardiomyocytes are key targets in AAV lamin-A therapy for Lmna-associated cardiac defects.

Cancer lncRNAs have been identified by both experimental and in silico methods. However, the current approaches for mining cancer lncRNAs are not sufficient and accurate. To deeply discover them, we focus on the core cancer driver lncRNAs (CDLs) which directly interact with cancer driver protein-coding genes. We investigated various aspects of cancer-related lncRNAs (CRLs), including their genomic locations, expression patterns, and their direct interactions with cancer driver protein-coding genes. We found that most CRLs located in cancer driver topologically associated domains (CDTs). Moreover, some CRLs showed a high tendency for co-expression and binding sites with cancer driver protein-coding genes. Utilizing these distinctive characteristics and integrating >4000 multi-omics data, we developed a pipeline CADTAD to unearth conserved candidate CDLs in pan-cancer, including 256 oncogenic lncRNAs, 177 tumor suppressive lncRNAs, and 75 dual-function lncRNAs, as well as some specific candidate CDLs in three individual cancer types and validated their cancer-related characteristics. Importantly, the function of 10 putative CDLs in prostate cancer was subsequently validated through cell studies. In light of these findings, our study offers a new perspective from the 3D genome to study the roles of lncRNAs in cancer. Furthermore, we provide a valuable set of potential lncRNAs that could deepen our understanding of the oncogenic mechanism of CDLs.### Competing Interest StatementThe authors have declared no competing interest.

CHD6, a member of the chromodomain helicase DNA-binding protein family, has been implicated in various diseases and tumors. However, its precise binding model of CHD6 on regulatory functional genes remains poorly understood. In this study, we discovered sharp peaks of CHD6, as the first member of CHD family for housekeeping process, binding only to the promoter region of genes in the C4-2 cell line. These genes, with conserved sharp CHD6 peaks across tumor cells, likely represent housekeeping genes ADNP and GOLGA5. Genes with sharp CHD6 peaks exhibit stable and low expression levels, sharing epigenetic features similar to housekeeping genes. Furthermore, this regulatory model also exists in both HEK293 cells and cardiomyocytes. Overall, the results of this study demonstrate that CHD6 binds to the promoter regions of housekeeping genes, regulating their histone modifications, chromatin structure, and gene expression.

Immunotherapy targeting tumor-associated macrophages (TAMs) is a promising approach to treating cancer. However, the limited drug targets and ambiguous mechanisms impede the development of clinical immunotherapy strategies. To elucidate the underlying processes involved in mononuclear phagocyte (MNP) infiltration and phenotypic changes in hepatocellular carcinoma (HCC), we integrated single-cell RNA-sequencing data from 100,030 cells derived from patients with HCC and healthy individuals and compared the phenotypes and origins of the MNPs in the tumor core, tumor periphery, adjacent normal tissue, and healthy liver samples. Using machine learning and multi-omics analyses, we identified 445 infiltration-associated genes and potential drug targets affecting this process. Through in vitro experiments, we found that the expression of macrophage migration inhibitory factor (MIF) is the upstream regulator of secreted phosphoprotein 1 (SPP1) and promote migration in TAMs. Our findings also indicate that MIF promotes tumor metastasis and invasion and is a promising potential target for treating HCC.

Derivation of human hepatocytes from pluripotent stem cells in vitro has important applications including cell therapy and drug discovery. However, the differentiation of pluripotent stem cells into hepatocytes in vitro was not well recapitulated the development of liver. Here, we developed a differentiation protocol by mimicking the two-stage development of hepatoblasts, which permits the efficient generation of hepatic progenitor cells from chemically induced pluripotent stem cells (hCiPSCs). Single-cell RNA sequencing (scRNA-seq) indicates the similarity between hepatoblasts differentiated in vitro and in vivo. Moreover, hCiPSC-derived hepatic progenitor cells can further differentiate into hepatocytes that are similar to primary human hepatocytes with respect to gene expression and key hepatic functions. Our results demonstrate the feasibility of generating hepatic progenitor cells and hepatocytes from hCiPSCs with high efficiency and set the foundation for broad translational applications of hCiPSC-derived hepatocytes.