The differentiation imbalance in bone marrow mesenchymal stem cells (BMMSCs) is critical for the development of bone density diseases as the population ages. BMMSCs are precursor cells for osteoblasts and adipocytes; however, the chromatin organization landscapes during BMMSC differentiation remain elusive. In this study, we systematically delineate the four-dimensional genome and dynamic epigenetic atlas of BMMSCs by RNA sequencing, assay for transposase-accessible chromatin sequencing, and high-throughput chromosome conformation capture. The structure analyses reveal 17.5% common and 28.5%-30% specific loops among BMMSCs, osteoblasts, and adipocytes. The subsequent correlation of genome-wide association studies and expression quantitative trait locus (eQTL) data with multi-omics analysis reveal 274 genes and 3634 single nucleotide polymorphisms (SNPs) associated with bone degeneration and osteoporosis (OP). We hypothesize that SNP mutations affect transcription factor (TF) binding sites, thereby affecting changes in gene expression. Furthermore, 26 motifs, 260 TFs, and 291 SNPs are identified to affect the eQTL. Among these genes, DAAM2, TIMP2, and TMEM241 are found to be essential for diseases such as bone degeneration and OP and may serve as potential drug targets.Copyright (c) 2023, The Authors. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).