Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging

Abstract

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

DNA Methylation Profiling for Diagnosing Undifferentiated Sarcoma with Capicua Transcriptional Receptor (CIC) Alterations

“…Global profiling methylation data were also compared to 32 samples randomly extracted from internal and external datasets [21] among those classifying as central nervous system neuroblastoma FOXR2 (CNS-NB-FOXR2), CIC rearranged sarcoma (EFT-CIC), high-grade neuroepithelial tumor MN1 (HGNET-MN1), and high-grade neuroepithelial tumor BCOR (HGNET-BCOR) using the Heidelberg brain tumor and sarcoma classifier. Bead Chip data were analyzed by means of R (V. 3.4.4) package minfi (V. 1.24.0) to obtain normalized beta values and to perform multidimensional scaling (MDS) analysis, as previously described [18][19][20]. Our patient displayed global methylation levels close to those of Ewing Family Tumor (EFT)-CIC, as evidenced by MDS performed on the 1000 most variable islands in the cohort (Figure 3).…”

“…These bioinformatics pipelines and classifiers use statistical tests and algorithms, such as random forest analyses, to make class predictions, exploiting advanced machine learning techniques. The main factor for the usefulness of DNA methylation profiling lies in the classification and clinical management of central nervous system tumors [19,21].…”

“…Tumor areas with the highest tumor cell content (≥70%) were selected for DNA extraction. Samples were analyzed using Illumina Infinium Human Methylation EPIC Bead Chip (EPIC) (Illumina, San Diego, CA, USA) arrays according to the manufacturer's instructions, as previously reported [18][19][20]. In detail, 500 ng DNA were used as input material for fresh frozen tissue.…”

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

“…In these conditions, neurological dysfunction and intellectual disability (ID) are common features; even though, a variable set of developmental processes affecting other organs and systems are also observed to co-occur [2]. Frameshift mutations affecting HIST1H1E (MIM *142220) have been causally linked to the so-called Rahman syndrome (RMNS, MIM #61753), a recently recognized developmental disorder characterized by mild to severe ID, a distinctive facial gestalt, variable somatic overgrowth which may manifest in early infancy but is not observed in adults, and an aging appearance [3,4]. As in the case of many neurodevelopmental disorders, RMNS exemplifies the challenges of reaching diagnosis on the basis of clinical criteria.…”

“…RMNS is caused by a narrow spectrum of functionally equivalent mutations affecting the C-terminus of HIST1H1E [3,4], which is a member of the H1 histone family functioning as a structural component of chromatin to control the extent of DNA compaction, regulation of gene expression and DNA replication, recombination, and repair [5][6][7][8]. Consistent with the pleiotropic impact of altered chromatin compaction, this class of HIST1H1E mutations was found to perturb multiple cellular processes resulting in cellular senescence and replicative impasse [4]. Notably, we and others previously observed that dysregulation and loss of HIST1H1E function affect genome methylation [4,8].…”