Page 1 \ ?^p 6r.1 CELL CYCLE CONTROL OF HUMAN H4 ...

Atiz F:Cettat -aCtuot o! Ha Gq.r'?Nnpti'
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o|Jl mutalonal anayses also show thal th€ rBcognition el€menls lor
HiNF P/H4TF-2, HiNF-O (CDc2/cydin A/RB_r6laled comPlex) or boih al€
only detectable as tatelimiing lor basal lranscriplion in th6 abs€nc€ ol a
lunctional H|NF-M/|RF.2 bind;ig sl€ 11 ls Possibl€
that €ach ol th6s€ taclors
operates via a simpla independenl and ps.haps mutlslly erclugve
transcriptional nechanism al Site ll, with €ach providing only a quantftanvely
mode$co ribution (10%ro 30%) lottu oveialll€v€lol H4 gene lransc.r on
Howsver, equally importanl is rh€ possibilily $at She ll proteins tundion in
conc€rl a.d that rhe rolative convibutions ol lh6s€ iransciptional acivities is
slroigly cell cycle $ag€ or cell typ€ d€Pendent Disctiminerion b6tween hes€
and o|her .elinemsrns ol models lor H4 gens lransdiption €quned tunh€r
experimenlalion However, the resLlLls clearly slgggst thar lh€ lundamenta
basis lor H4 qene regllarron by si€ ll €n noi b€ a$ribul€d io |he aclon ol
one panicula. histon€ subtype_specilic lador al a singular €rement' as h6s
been proposed lor seve.a other human hislone genes (Heinlz, 1991) Falh6r'
the integrated aclivities oi mulliple transc.ipnon laclors at a comoos'le
regulatory doman logether elgvale H4 gene vansc ption in difierenl
proliierating cells expressing ditinct tissue_specilic and cell Orov{h 'elaied
phenovpic Prope.lLes
The experiments described ln this hesis were airned at understanding
lhe comibuton ol H4 gene promoier sile ll sequenes and lhe cognare
iactors io cell cycle comroLbd rranscridion ol the H4 ge's arhouqh our
reslLtsclearly mdicale dramatic qlantita ve efiecls ol HNF M/|FF'2 o' Site ll