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Vol. 18, Issue 2, 348-361, February 2007

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NuMA Influences Higher Order Chromatin Organization in Human Mammary Epithelium

Patricia C. Abad^*, Jason Lewis^*, I. Saira Mian, David W. Knowles, Jennifer Sturgis^*, Sunil Badve, Jun Xie, and Sophie A. Lelièvre^*

*Department of Basic Medical Sciences and Cancer Center, Purdue University, West Lafayette, IN 47907-2026; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720-8268; Indiana University School of Medicine, Indianapolis, IN 46202-5280; and Department of Statistics, Purdue University, West Lafayette, IN 47907-2067

Submitted June 26, 2006; Revised October 30, 2006; Accepted November 3, 2006
Monitoring Editor: A. Gregory Matera

The coiled-coil protein NuMA is an important contributor to mitotic spindle formation and stabilization. A potential role for NuMA in nuclear organization or gene regulation is suggested by the observations that its pattern of nuclear distribution depends upon cell phenotype and that it interacts and/or colocalizes with transcription factors. To date, the precise contribution of NuMA to nuclear function remains unclear. Previously, we observed that antibody-induced alteration of NuMA distribution in growth-arrested and differentiated mammary epithelial structures (acini) in three-dimensional culture triggers the loss of acinar differentiation. Here, we show that in mammary epithelial cells, NuMA is present in both the nuclear matrix and chromatin compartments. Expression of a portion of the C terminus of NuMA that shares sequence similarity with the chromatin regulator HPC2 is sufficient to inhibit acinar differentiation and results in the redistribution of NuMA, chromatin markers acetyl-H4 and H4K20m, and regions of deoxyribonuclease I-sensitive chromatin compared with control cells. Short-term alteration of NuMA distribution with anti-NuMA C-terminus antibodies in live acinar cells indicates that changes in NuMA and chromatin organization precede loss of acinar differentiation. These findings suggest that NuMA has a role in mammary epithelial differentiation by influencing the organization of chromatin.

Address correspondence to: Sophie A. Lelièvre (lelievre{at}purdue.edu)

Abbreviations used: acetyl-H4, acetylated histone 4; CSK, cytoskeleton buffer, CSK; CT, C terminus; DNase, deoxyribonuclease; DAPI, 4',6-diamidino-2-phenylindole dihydrochloride:hydrate; H4K20m, histone 4 methylated on lysine 20; HMEC, human mammary epithelial cells; LBF, local bright feature; MAR, matrix attachment region; NLS, nuclear localization signal; NuMA, nuclear mitotic apparatus protein; PI, protein and phosphatase inhibitors; 3D, three-dimensional; TBS, Tris-buffered saline; TBST, Tris-buffered saline with Tween; 2D, two-dimensional

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