Biology subjects

Lian, J. B.

Publications and source records attributed to Lian, J. B..

4 recordsLinked to original sources

bioRxiv2022

Sustained morphine delivery suppresses bone formation and alters metabolic and circulating miRNA profiles in male C57BL/6J mice

Opioid use is detrimental to bone health, causing both indirect and direct effects on bone turnover. While the mechanisms of these effects are not entirely clear, recent studies have linked chronic opioid use to alterations in circulating miRNAs. Our aim was to develop a model of opioid-induced bone loss to understand bone turnover and identify candidate miRNA-mediated regulatory mechanisms. We evaluated the effects of sustained morphine treatment on the skeleton, metabolism, and body composition of male and female C57BL/6J mice by treating with vehicle (0.9% saline) or morphine (18 mg/kg) using subcutaneous osmotic minipumps for 25 days. Morphine-treated mice had higher energy expenditure and respiratory quotient, indicating a shift toward carbohydrate metabolism. Microcomputed tomography ({micro}CT) analysis indicated that male mice treated with morphine had reduced trabecular bone volume fraction (Tb.BV/TV) (15%) and Tb. bone mineral density (BMD) (14%) in the distal femur compared to vehicle. Conversely, bone microarchitecture was not changed in females after morphine treatment. Histomorphometric analysis demonstrated that in males, morphine reduced bone formation rate compared to vehicle, but osteoclast parameters were not different. Furthermore, morphine reduced bone formation marker gene expression in the tibia of males (Bglap and Dmp1). Circulating miRNA profile changes were evident in males, with 14 differentially expressed miRNAs associated with morphine treatment. Target analysis indicated hypoxia inducible factor (HIF) signaling pathway was targeted by miR-223-3p and fatty acid metabolism by miR-484, - 223-3p, and -328-3p. In summary, we have established a model where morphine leads to a lower trabecular bone formation in males. Further, understanding the mechanisms of bone loss from opioid treatment will be important for improving management of the adverse effects of opioids on the skeleton.

physiology↗

bioRxiv2021

Pathogenic mutations in the chromokinesin KIF22 disrupt anaphase chromosome segregation

The chromokinesin KIF22 generates forces that contribute to mitotic chromosome congression and alignment. Mutations in the 2 helix of the motor domain of KIF22 have been identified in patients with abnormal skeletal development, and we report the identification of a patient with a novel mutation in the KIF22 tail. We demonstrate that pathogenic mutations do not result in a loss of KIF22s functions in early mitosis. Instead, mutations disrupt chromosome segregation in anaphase, resulting in reduced proliferation, abnormal daughter cell nuclear morphology, and, in a subset of cells, cytokinesis failure. This phenotype could be explained by a failure of KIF22 to inactivate in anaphase. Consistent with this model, constitutive activation of the motor via a known site of phosphoregulation in the tail phenocopied the effects of pathogenic mutations. These results suggest the motor domain 2 helix may be an important site for regulation of KIF22 activity at the metaphase to anaphase transition. In support of this conclusion, mimicking phosphorylation of 2 helix residue T158 also prevents inactivation of KIF22 in anaphase. These findings demonstrate the importance of both the head and tail of the motor in regulating the activity of KIF22 and offer insight into the cellular consequences of preventing KIF22 inactivation and disrupting force balance in anaphase.

cell biology↗

bioRxiv2019

Mitotic gene bookmarking by RUNX1 contributes to stabilization of the normal mammary epithelial phenotype

RUNX1 has recently been shown to play an important role in determination of mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal transition (EMT) are not known. Here, we report mitotic bookmarking of genes by RUNX1 as a potential mechanism to convey regulatory information through successive cell divisions for coordinate control of mammary cell proliferation, growth, and identity. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and early G1 breast epithelial cells reveal RUNX1 is retained during the mitosis to G1 transition on protein coding and long non-coding RNA genes critical for mammary epithelial proliferation, growth, and phenotype maintenance. Disruption of RUNX1 DNA binding and association with mitotic chromosomes alters cell morphology, global protein synthesis, and phenotype-related gene expression. Together, these findings show for the first time that RUNX1 bookmarks a subset of epithelial-related genes during mitosis that remain occupied as cells enter the next cell cycle. Compromising RUNX1 DNA binding initiates EMT, an essential first step in the onset of breast cancer. SignificanceThis study elucidates mitotic gene bookmarking as a potential epigenetic mechanism that impacts breast epithelial cell growth and phenotype and has potential implications in breast cancer onset.

cancer biology↗

bioRxiv2018

RUNX1 suppresses breast cancer stemness and tumor growth

Recent studies have revealed that mutations in the transcription factor Runx1 are prevalent in breast tumors. Yet, how loss of Runx1 contributes to breast cancer (BCa) remains unresolved. We demonstrate for the first time that Runx1 represses the breast cancer stem cell (BCSC) phenotype and consequently, functions as a tumor suppressor in breast cancer. Runx1 ectopic expression in MCF10AT1 and MCF10CA1a BCa cells reduces (60%) migration, invasion and in vivo tumor growth in mouse mammary fat pad (P<0.05). Runx1 is decreased in BCSCs, and overexpression of Runx1 suppresses tumorsphere formation and reduces the BCSC population. Furthermore, Runx1 inhibits Zeb1 expression, while Runx1 depletion activates Zeb1 and the epithelial-mesenchymal transition. Mechanistically Runx1 functions as a tumor suppressor in breast cancer through repression of cancer stem cell activity. This key regulation of BCSCs by Runx1 may be shared in other epithelial carcinomas, highlighting the importance of Runx1 in solid tumors.

cancer biology↗